Polar substituted hydrocarbons

ABSTRACT

The invention relates to retroviral protease inhibitors of the general formula (I): W--(A) n  --B--(A*) m  --V where W, A, B, A*, V, n and m are as defined herein, including related prodrugs of general formula (I) comprising a solubilizing group which is labile in vivo.

This application is a national stage filing of PCT/AU94/00538 filed Sep.12, 1994 which claims priority to Australian application numbers PM 6446and PM 1161 filed Jun. 24, 1994 and Sep. 10, 1993 respectively, and acontinuation-in-part application of U.S. Ser. No. 08/295,855, filed Nov.11, 1994, now U.S. Pat. No. 5,679,688, which is a nation stage filing ofPCT/AU93/00103 filed Mar. 11, 1993, which claims priority to Australianapplication number PL 1304 file Mar. 11, 1992.

TECHNICAL FIELD

The invention relates to certain hydrocarbon derivatives bearing polarsubstituents and their use in the inhibition of retroviral proteases,for example in the treatment of HIV viral infections such as acquiredimmunodeficiency syndrome (AIDS). The invention also relates toprocesses for preparing such hydrocarbon derivatives bearing polarsubstituents, to pharmaceutical compositions comprising them and tomethods for the treatment or prophylaxis of retroviral infections. Theinvention also relates to a process for enhancing the water-solubilityof a pharmaceutical or veterinary substance.

BACKGROUND ART

Human immunodeficiency virus (HIV) is a pathogenic retrovirus causingAIDS and its related disorders. The development of antiviralchemotherapy against AIDS has been the subject of an intense researcheffort since the discovery of HIV. (For a recent review on moleculartargets for AIDS therapy see Mitsua et al, Science, 1990, pp 1533-1544).The HIV Proteases (HIV PR), and aspartyl proteases, were first suggestedas a potential target for AIDS therapy by Kramer et al. (Science 231,1580 (1986)). Since that time the potential usefulness of HIV PRinhibitors as effective agents in treatment of AIDS has been widelyrecognized (for a review of the HIV PR as a therapeutic target seeTomaselli et al. Chimica Oggi, May 1991, pp 6-27 and Huff J. R., J. Med.Chem. 34, 2314-2327 (1991)). Of the classical transition state mimicsfor aspartyl proteases, the hydroxyethylene, dihydroxyethylene,hydroxyethylamine and phosphinic acid isosteres appear to provide thegreatest affinity for HIV PR. Many inhibitors of HIV PR have been shownto have an antiviral activity at concentrations in the nanomolar rangein the different cell systems and are described as such in the patentliterature.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide compounds useful asretroviral protease inhibitors. It is another object of the presentinvention to provide pharmaceutical compositions comprising compoundsuseful for the treatment or prophylaxis of retroviral infections. It isa further object of the present invention to provide methods for thetreatment or prophylaxis of retroviral infections, in particular AIDS.Other objects of the present invention are to provide processes forpreparing compounds useful as retroviral protease inhibitors, andprocesses for enhancing the water-solubility of pharmaceutical orveterinary substances, in particular retroviral protease inhibitors.

SUMMARY OF THE INVENTION

The invention provides compounds which are useful as inhibitors ofretroviral proteases, particularly aspartyl proteases and moreparticularly HIV proteases, and which are effective in treatingconditions characterized by unwanted activity of these enzymes, inparticular acquired immune deficiency syndrome.

In the following description of the invention, the teaching of each ofthe publications mentioned is incorporated herein by reference.

A first embodiment of the invention is directed to compounds of thegeneral formula or pharmaceutically acceptable salts or prodrugsthereof:

    W--(A).sub.n --B--(A*).sub.m --V                           (I)

wherein

W is selected from the group consisting of R₁ --X--, R_(1*) --X*--,--Y*, --CN, --N═CR₅ R_(5*), --C(R₅)═NR₃, --C(R₅)═NOR₃, --C(NR₃R₄)═NR_(5**), C(D)OR₃, --C(D)SR₃ and --C(D)NR₃ R₄, wherein

Y* is as defined below,

R₁, R₃ and R₄ are independently selected from the group consisting of R₆and a solubilising group Px which is labile in vivo, wherein R₆ isselected from the group consisting of

hydrogen,

R₂₀, wherein R₂₀ is selected from the group consisting of

optionally substituted (C₁ -C₁₈)alkyl,

optionally substituted (C₂ -C₁₈)alkenyl,

optionally substituted (C₂ -C₁₈)alkynyl,

optionally substituted (C₃ -C₁₈)cycloalkyl,

optionally substituted (C₃ -C₁₈)cycloalkyl(C₁ -C₁₈)alkyl,

optionally substituted (C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkenyl,

optionally substituted (C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkynyl,

optionally substituted (C₆ -C₂₄)aryl,

optionally substituted (C₆ -C₂₄)aryl(C₁ -C₁₈)alkyl,

optionally substituted (C₆ -C₂₄)aryl(C₂ -C₁₈)alkenyl,

optionally substituted (C₆ -C₂₄)aryl(C₂ -C₁₈)alkynyl,

optionally substituted (C₁ -C₁₈)acyl,

optionally substituted heterocyclic,

optionally substituted heterocyclic(C₁ -C₁₈)alkyl,

optionally substituted heterocyclic(C₂ -C₁₈)alkenyl, and

optionally substituted heterocyclic(C₂ -C₁₈)alkynyl

C(D)OR₂₁,

C(D)SR₂₁,

C(D)NR₂₁ R₂₂,

C(NR₂₁)R₂₂,

C(NR₂₁)OR₂₂, and

C(NR₂,)NR₂₂ R₂₃, wherein R₂₁, R₂₂ and R₂₃ independently are selectedfrom hydrogen and R₂₀ as previously defined, or R₂₁ and R₂₂ together, orR₂₂ and R₂₃ together form a saturated or unsaturated cyclic, bicyclic orfused ring system as defined below,

or R₃ and R₄, when present, together form a saturated or unsaturatedcyclic, bicyclic or fused ring system as defined below,

D is selected from O and S,

X is selected from the group consisting of Y, S(O) and S(O)₂ wherein Yis as defined below,

X* is selected from the group consisting of NR₁₀, O and S, wherein R₁₀has the meaning of R₆ as previously defined,

R_(1*) is selected from the group consisting of R₁ as previouslydefined, P(O)(OR₇)R₈, S(O)_(z) OR₇ and S(O)_(z) NR₇ R₈, wherein z is 1or 2 and R₇ and R₈ independently have the meaning of R₂₀ as previouslydefined, or R₇ and R₈ together form a saturated or unsaturated cyclic,bicyclic or fused ring system as defined below,

R₅ and R_(5*) are independently selected from the group consisting of H,CF₃, C(D)OR₁₀₃, C(D)SR₁₀₃ C(D)NR₁₀₃ R₁₀₄ and R₂₀ as previously defined,wherein D is as previously defined, and wherein R₁₀₃ and R₁₀₄ have themeaning of R₆ as previously defined, or R₁₀₃ and R₁₀₄ together form asaturated or unsaturated cyclic, bicyclic or fused ring system asdefined below, and

R_(5**) is selected from hydrogen and R₂₀ as previously defined ;

n is 0-6;

m is 0-6and n+m>1;

A at each occurrence is independently selected from the group consistingof ##STR1## and a residue of a naturally occurring or synthetic aminoacid; A* at each occurrence is independently selected from the groupconsisting of ##STR2## and a residue of a naturally occurring orsynthetic amino acid; wherein R_(12*), R_(13*), R₉ and R_(9*) areindependently selected from the group consisting of F, Cl, Br, I and R₅as previously defined,

R₁₁ has the meaning of R₁ as previously defined,

R₁₂ has the meaning of R₆ as previously defined,

R₁₃ is selected from the group consisting of

F, Cl, Br, I, R₆ as previously defined, and R₂₀₀, wherein R₂₀₀ isselected from the group consisting of

CN,

NCO,

NCS,

OCN,

SCN,

N₃,

OR₆₀,

SR₆₀,

NR₆₀ R₆₁,

D₁ C(D₂)R₆₀,

D₁ C(D₂)D₃ R₆₀,

D₁ C(D₂)NR₆₀ R₆₁,

NR₆₀ C(D₁)R₆₁,

NR₆₀ C(D₁)D₂ R₆₁,

NR₆₀ C(D₁)NR₆₁ R₆₂,

NR₆₀ OR₆,

amidino,

guanidino,

S(O)R₆₀,

S(O)₂ D₁ R₆₀,

S(O)NR₆₀ R₆₁,

S(O)₂ NR₆₀ R₆₁,

D₁ S(O)R₆₀,

D₁ S(O)₂ OR₆₀,

D₁ S(O)NR₆ OR₆₁,

D₁ S(O)₂ NR₆₀ R₆₁,

P(D₁)(D₂ R₆₀)R₆₁ ,

P(D₁)(D₂ R₆₀)D₃ R₆₁,

P(D₁) (D₂ R₆₀)NR₆₁ R₆₂,

P(D₁)R₆₀ R₆₁,

D₁ P(D₂)(D₃ R₆₀)R₆₁,

D₁ P(D₂)(D₃ R₆₀)D₄ R₆₁,

D₁ P(D₂)(D3R₆₀)NR₆₁ R₆₂,

D₁ P(D₂)R₆₀ R₆₁,

NR₆₀ NR₆₁ R₆₂ and

ONR₆₀ R₆₁, wherein D₁, D₂, D₃ and D₄ independently have the meaning of Das previously defined, and R₆₀, R₆₁, and R₆₂ independently have themeaning of R₆ as previously defined or any two or more of R₆₀, R₆₁, andR₆₂ form part of a saturated or unsaturated cyclic, bicyclic or fusedring system as defined below,

or R₁₂ and R₁₃ together are selected from the group consisting of ═O,═S, ##STR3## wherein Q is optionally substituted (C₁ -C₁₂)alkylidene asdefined below and R₆₀ is as previously defined, and

L is selected from the group consisting of a bond, ##STR4## --CH₂ -- and--CH₂ --CH₂ --, wherein R₁₁ and D are as previously defined, R_(11*) andD* have the meaning of R₁₁ and D respectively, and z is 1 or 2;

R_(13**) is F, Cl, Br, OR₆₀ or NR₆₀ R₆₀ wherein R₆₀ and R₆₁ are aspreviously defined,

B is selected from the group consisting of ##STR5## wherein R₂₀₃ andR_(203*) independently have the meaning of R₆ as previously defined,

R_(14*) and R_(14**) are independently selected from the groupconsisting of hydrogen,

R₂₀ as previously defined,

CF₃,

C(D*)OR₄₀,

C(D*)SR₄₀ and

C(D*)NR₄₀ R₄₁, wherein R₄₀ and R₄₁, independently have the meaning ofR₂₁ and R₂₂ as previously defined or R₄₀ and R₄₁ form part of asaturated or unsaturated cyclic, bicyclic or fused ring system asdefined below,

R₁₄ is selected from the group consisting of F, Cl, Br, I, R_(14*) aspreviously defined and R₂₀₀ as previously defined,

R₁₇ and R_(17*) independently have the meaning of R₆ as previouslydefined,

D* has the meaning of D as previously defined,

Z is a saturated or unsaturated (C₂ -C₄)alkylidene radical which isoptionally substituted with one or more groups selected from F, Cl, Br,I and R_(14*) as previously defined,

Z* is a saturated or unsaturated (C₁ -C₃)alkylidene radical which isoptionally substituted with one or more groups selected from F, Cl, Br,I and R_(14*) as previously defined,

M₁ is selected from the group consisting of OR₁₅, SR₁₅ and NR₁₅ R₁₇,wherein R₁₅ is selected from the group consisting of:

Px as previously defined, and

R₆ as previously defined, and

a glycosyl radical which is derived from a synthetic or naturallyoccurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose,aminoketose or an oligosaccharide thereof, and

R₁₇ is as previously defined, or

R₁₅ and R₁₇ together form a saturated or unsaturated cyclic, bicyclic orfused ring system as defined below,

M and M* are independently selected from the group consisting of M₁ aspreviously defined, OCN, SCN, YR₂, Y* and N=CR₃₀ R₃₁, wherein Y, Y* andR₂ are as defined below, and R₃₀ and R₃₁ independently have the meaningof R₂₀ as previously defined,

M₂ is selected from the group consisting of R_(14*) as previouslydefined, --CR_(30*) ═Y** and --CR_(30*) ═NR_(17*), where Y** is asdefined below, R_(30*) has the meaning of R₂₀ as previously defined, andR_(17*) is as previously defined,

R₁₈ and R₁₉ independently have the meaning of R₂₀ as previously definedor R₁₈ and R₁₉ together form part of a saturated or unsaturated cyclic,bicyclic or fused ring system as defined below, and

R_(18*) and R_(19*) together form part of a saturated or unsaturatedcyclic, bicyclic or fused ring system as defined below;

V is selected from the group consisting of YR₂, Y* and C(R₃₀)═Y**,wherein

Y is absent or is selected from the group consisting of: 0. ##STR6##wherein D** is selected from the group consisting of a bond, O, S andNR₅₀, R₅₀ has the meaning of R₆ as previously defined, R₅₁ has themeaning of R₁₅ a previously defined and R₅₂ has the meaning of R₂₀ aspreviously defined, or R₅₀ and R₅₁, when present, together form part ofa saturated or unsaturated cyclic, bicyclic or fused ring system asdefined below, and

R₂ has the meaning of R₆ as previously defined,

Y* is selected from the group consisting of ##STR7## wherein D* and D**independently have the meaning of D as previously defined ; R_(114*),R_(114**), R₁₁₅ and R_(117*) have the meaning of R_(14*), R_(14**), R₁₅and R_(17*) respectively, as previously defined ; R₅₀ and R₅₁ are aspreviously defined or R₅₀ and R₅₁ together form part of a saturated orunsaturated cyclic, bicyclic or fused ring system as defined below;R_(2*) is selected from the group consisting of R₂ as previouslydefined, Px as previously defined, S(O)_(z) OR₁₂₀ and S(O)_(z) NR₁₂₀R₁₂₁, wherein z is 1 or 2; R₃₃ and R₃₄ are independently selected fromthe group consisting of hydrogen and R₂₀ as previously defined, or R₃₃and R₃₄ together form a saturated or unsaturated cyclic, bicyclic orfused ring system as defined below, and R₁₂₀ and R₁₂₁ independently havethe meaning of R₂₀ as previously defined, or R₁₂₀ and R₁₂₁ together forma saturated or unsaturated cyclic, bicyclic or fused ring system asdefined below,

R₃₀ is as previously defined, and

Y** is selected from ═N--NR₁₁₅ R₁₁₇ and ═N--OR₁₁₅, wherein R₁₁₅ and R₁₁₇have the meaning of R₁₅ and R₆ respectively, as previously defined, orR₁₁₅ and R₁₁₇ together form a saturated or unsaturated cyclic, bicyclicor fused ring system as defined below, and wherein any group selectedfrom R₁, R_(1*), R₂, R_(2*), R₉, R₁₁, R₁₂, R₁₃, R₁₄, R_(14*), R₁₇, R₅₀and R₅₁ may, together with any other group selected from R₁, R_(1*), R₂,R_(2*), R_(9*), R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R_(14*), R₁₇, R₅₀ and R₅₁ formone or more saturated or unsaturated cyclic, bicyclic or fused ringsystem(s) as defined below, and wherein any tertiary amino nitrogen atommay be replaced by the group ##STR8## and, wherein any hydroxyl,mercapto or amino group may be protected by a protecting group which islabile in vivo.

Compounds of the general formula (I) are useful as inhibitors ofretroviral proteases, in particular HIV proteases.

One form of the first embodiment of the invention is directed tocompounds of the general formula (I') or pharmaceutically acceptablesalts or prodrugs thereof:

    W'--(A).sub.n' --B'--(A'*).sub.m' --V'                     (I')

wherein

W' is selected from the group consisting of R₁ --X--, R_(1*) --X*--,--Y*, --CN, --N═CR₅ R_(5*), --C(R₅)═NR₃, --C(R₅) ═NOR₃, --C(D)OR₃,--C(D)SR₃ and --C(D)NR₃ R₄, wherein

Y* is as defined below,

R₁, R₃ and R₄ are independently selected from the group consisting of R₆and a solubilising group Px which is labile in vivo, wherein R₆ isselected from the group consisting of

hydrogen,

R₂₀, wherein R₂₀ is selected from the group consisting of

optionally substituted (C₁ -C₁₈)alkyl,

optionally substituted (C₂ -C₁₈)alkenyl,

optionally substituted (C₂ -C₁₈)alkynyl,

optionally substituted (C₃ -C₁₈)cycloalkyl,

optionally substituted (C₃ -C₁₈)cycloalkyl(C₁ -C₁₈)alkyl,

optionally substituted (C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkenyl,

optionally substituted (C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkynyl,

optionally substituted (C₆ -C₂₄)aryl,

optionally substituted (C₆ -C₂₄)aryl(C₁ -C₁₈)alkyl,

optionally substituted (C₆ -C₂₄)aryl(C₂ -C₁₈)alkenyl,

optionally substituted (C₆ -C₂₄)aryl(C₂ -C₁₈)alkynyl,

optionally substituted (C₁ -C₁₈)acyl,

optionally substituted heterocyclic,

optionally substituted heterocyclic(C₁ -C₁₈ )alkyl,

optionally substituted heterocyclic(C₂ -C₁₈)alkenyl, and

optionally substituted heterocyclic(C₂ -C₁₈)alkynyl

C(D)OR₂₁,

C(D)SR₂₁, and

C(D)NR₂₁ R₂₂, wherein R₂, and R₂₂ independently are selected fromhydrogen and R₂₀ as previously defined, or R₂, and R₂₂ together form asaturated or unsaturated cyclic, bicyclic or fused ring system asdefined below,

or R₃ and R₄, when present, together form a saturated or unsaturatedcyclic, bicyclic or fused ring system as defined below,

D is selected from O and S,

X is selected from the group consisting of Y', S(O) and S(O)₂ wherein Y'is as defined below,

X* is selected from the group consisting of NR₁₀, O and S, wherein R₁₀has the meaning of R₆ as previously defined,

R_(1*) is selected from the group consisting of R₁ as previouslydefined, S(O)_(z) OR₇ and S(O)_(z) NR₇ R₈, wherein z is 1 or 2 and R₇and R₈ independently have the meaning of R₂₀ as previously defined, orR₇ and R₈ together form a saturated or unsaturated cyclic, bicyclic orfused ring system as defined below,

R₅ and R_(5*) are independently selected from the group consisting of H,CF₃, C(D)OR₁₀₃, C(D)SR₁₀₃ C(D)NR₁₀₃ R₁₀₄ and R₂₀ as previously defined,wherein D is as previously defined, and wherein R₁₀₃ and R₁₀₄ have themeaning of R₆ as previously defined, or R₁₀₃ and R₁₀₄ together form asaturated or unsaturated cyclic, bicyclic or fused ring system asdefined below;

n' is 0-8;

m' is 0-8 and n'+m'≧1;

A' and A'* are independently at each occurrence selected from the groupconsisting of O, S, S(O), S(O)₂, NR₁₁, CR₁₂ R₁₃ and CR_(12*) R_(13*), ortwo consecutive groups A'--A' or A'*--A'* are a structural unit selectedfrom ##STR9## wherein and R_(12*), R_(13*), R₉ and R_(9*) areindependently selected from the group consisting of F, Cl, Br, I and R₅as previously defined,

R₁₁, has the meaning of R₁ as previosly defined,

R₁₂ has the meaning of R₆ as previously defined,

R₁₃ is selected from the group consisting of

F, Cl, Br, I, R₆ as previously defined, and R₂₀₀, wherein R₂₀₀ isselected from the group consisting of

CN,

NCO,

NCS,

OCN,

SCN,

N₃,

OR₆₀,

D₁ C(D₂)R₆₀,

D₁ C(D₂)D₃ R₆₀,

D₁ C(D₂)NR₆₀ R₆₁,

NR₆₀ C(D)R₆₁,

NR₆₀ C(D₁)D₂ R₆₁,

NR₆₀ C(D₁)NR₆₁ R₆₂,

NR₆₀ OR₆₁,

amidino,

guanidino,

S(O)R₆₀,

S(O)₂ D₁ R₆₀,

S(O)NR₆₀ R₆₁,

S(O)₂ NR₆₀ R₆₁,

D₁ S(O)R₆₀,

D₁ S(O)₂ OR₆₀,

D₁ S(O)NR₆₀ R₆₁,

D₁ S(O)₂ NR₆₀ R₆₁,

P(D₁)(D₂ R₆₀)R₆₁,

P(D₁)(D₂ R₆₀)D₃ R₆₁,

P(D₁)(D₂ R₆₀)NR₆₁ R₆₂,

P(D₁)R₆₀ R₆₁,

D₁ P(D₂)(D₃ R₆₀)R₆₁,

D₁ P(D₂)(D₃ R₆₀)D₄ R₆₁,

D₁ P(D₂)(D₃ R₆)NR₆₁ R₆₂,

D₁ P(D₂)R₆₀ R₆₁,

NR₆₀ NR₆₁ R₆₂ and

ONR₆₀ R₆₁, wherein D₁, D₂, D₃ and D₄ independently have the meaning of Das previously defined, and R₆₀, R₆₁ and R₆₂ independently have themeaning of R₆ as previously defined or any two or more of R₆₀, R₆₁, andR₆₂ form part of a saturated or unsaturated cyclic, bicyclic or fusedring system as defined below, or R₁₂ and R₁₃ together are selected fromthe group consisting of ═O, ═S, ═NOR₆₀, ═NR₆₀, --OQO--, --SQS-- and--SQO--, wherein Q is optionally substituted (C₁ -C₁₂)alkylidene asdefined below and R₆₀ is as previously defined ;

B' is selected from the group consisting of ##STR10## wherein R₂₀₃ andR_(203*) independently have the meaning of R₆ as previously defined,

R_(14*) and R_(14**) are independently selected from the groupconsisting of hydrogen,

R₂₀ as previously defined,

CF₃,

C(D*)OR₄₀,

C(D*)SR₄₀ and

C(D*)NR₄₀ R₄₁, wherein R₄₀ and R₄₁ independently have the meaning of R₂₁and R₂₂ as previously defined or R₄₀ and R₄₁ form part of a saturated orunsaturated cyclic, bicyclic or fused ring system as defined below,

R₁₄ is selected from the group consisting of F, Cl, Br, I, R_(14*) aspreviously defined and R₂₀₀ as previously defined,

R₁₇ and R_(17*) independently have the meaning of R₆ as previouslydefined,

D* has the meaning of D as previously defined,

Z is a saturated or unsaturated (C₂ -C₄)alkylidene radical which isoptionally substituted with one or more groups selected from F, Cl, Br,I and R₁₄ * as previously defined,

Z* is a saturated or unsaturated (C₁ -C₃)alkylidene radical which isoptionally substituted with one or more groups selected from F, Cl, Br,I and R₁₄ * as previously defined,

M₁ is selected from the group consisting of OR₁₅, SR₁₅ and NR₁₅ R₁₇,

wherein R₁₅ is selected from the group consisting of:

Px as previously defined,

R₆ as previously defined, and

a glycosyl radical which is derived from a synthetic or naturallyoccurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose,aminoketose or an oligosaccharide thereof, and

R₁₇ is as previously defined, or

R₁₅ and R₁₇ together form a saturated or unsaturated cyclic, bicyclic orfused ring system as defined below,

M and M* are independently selected from the group consisting of M₁ aspreviously defined, OCN, SCN, Y'R₂, Y* and N═CR₃₀ R₃₁, wherein Y', Y*and R₂ are as defined below, and R₃₀ and R₃₁ independently have themeaning of R₂₀ as previously defined,

M₂ is selected from the group consisting of R_(14*) as previouslydefined, --CR_(30*) ═Y** and --CR_(30*) ═NR_(17*), where Y** is asdefined below, R_(30*) has the meaning of R₂₀ as previously defined, andR_(17*) is as previously defined,

R₁₈ and R₁₉ independently have the meaning of R₂₀ as previously definedor R₁₈ and R₁₉ together form part of a saturated or unsaturated cyclic,bicyclic or fused ring system as defined below, and

R_(18*) and R_(19*) together form part of a saturated or unsaturatedcyclic, bicyclic or fused ring system as defined below;

V' is selected from the group consisting of Y'R₂, Y* and C(R₃₀)═Y**,wherein

Y' is selected from the group consisting of ##STR11## wherein R₅₀ hasthe meaning of R₆ as previously defined, R₅₁ has the meaning of R₁₅ aspreviously defined and R₅₂ has the meaning of R₂₀ as previously defined,or R₅₀ and R₅₁ together form part of a saturated or unsaturated cyclic,bicyclic or fused ring system as defined below, and

R₂ has the meaning of R₆ as previously defined,

Y* is selected from the group consisting of ##STR12## wherein D* and D**independently have the meaning of D as previously defined; R_(114*),R_(114**), R₁₁₅ and R_(117*) have the meaning of R_(14*), R_(14**), R₁₅and R_(17*) respectively, as previously defined; R₅₀ and R₅₁ are aspreviously defined or R₅₀ and R₅₁ together form part of a saturated orunsaturated cyclic, bicyclic or fused ring system as defined below;R_(2*) is selected from the group consisting of R₂ as previouslydefined, S(O)_(Z) OR₁₂₀ and S(O)_(Z) NR₁₂₀ R₁₂₁, wherein z is 1 or 2;R₃₃ and R₃₄ are independently selected from the group consisting ofhydrogen and R₂₀ as previously defined, or R₃₃ and R₃₄ together form asaturated or unsaturated cyclic, bicyclic or fused ring system asdefined below, and R₁₂₀ and R₁₂₁ independently have the meaning of R₂₀as previously defined, or R₁₂₀ and R₁₂₁ together form a saturated orunsaturated cyclic, bicyclic or fused ring system as defined below,

R₃₀ is as previously defined, and

Y** is selected from ═N--NR₁₁₅ R₁₁₇ and ═N--OR₁₁₅, wherein R₁₁₅ and R₁₁₇have the meaning of R₁₅ and R₆ respectively, as previously defined, orR₁₁₅ and R₁₁₇ together form a saturated or unsaturated cyclic, bicyclicor fused ring system as defined below,

and wherein any group selected from R₁, R_(1*), R₂, R_(2*), R₉, R₁₁,R₁₂, R₅₀ and R₅₁ may, together with any other group selected from R₁,R_(1*), R₂, R_(2*), R_(9*), R₁₀, R₁₁, R₁₂, R₅₀ and R₅₁ form one or moresaturated or unsaturated cyclic, bicyclic or fused ring system(s) asdefined below,

and wherein any tertiary amino nitrogen atom may be replaced by thegroup ##STR13## and, where the sequence W'--(A')_(n) '--B'--(A'*)_(m)'--V' contains a grouping of three heteroatoms together, one atom ofthose three heteroatoms is oxidised sulfur in the form of S(O) or S(O)₂,or oxidised phosphorus in the form of P(O), or the three heteroatomscomprise two nitrogen atoms which form part of a heterocycle, providedthat the sequence W'--(A')_(n) '--B'--(A'*)_(m) '--V' does not containtwo oxygen. atoms together or three sulfur atoms together;

and wherein (a) when W' is R_(1*) X* wherein X* is NR₁₀, and V' is Y*wherein Y* is ##STR14## and B' is ##STR15## wherein R₈₁ is selected fromthe group consisting of hydrogen, --R₁₀₀ H, --R₁₀₀ C(O)OR₁₀₁, --R₁₀₀C(O)NR₁₀₁ R₁₀₂, --R₁₀₀ NR₁₀₂ C(O)R_(100*) and --R₁₀₀ C(O)R_(100*),

wherein R₁₀₁ and R₁₀₂ are independently selected from the groupconsisting of hydrogen, optionally substituted (C₁ -C₁₈)alkyl,optionally substituted (C₃ -C₁₈)cycloalkyl, optionally substituted (C₃-C₁₈)cycloalkyl-(C₁ -C₁₈)alkyl, optionally substituted (C₆ -C₂₄)aryl,optionally substituted (C₇ -C₂₅)aralkyl, optionally substituted (C₂-C₁₈)alkenyl, optionally substituted (C₈ -C₂₆)-aralkenyl, optionallysubstituted (C₂ -C₁₈)-alkynyl, optionally substituted (C₈-C₂₆)-aralkynyl and optionally substituted heterocyclic,

and wherein R₁₀₀ and R_(100*) are independently divalent radicalsderived from a member selected from the group consisting of (C₁-C₁₈)alkyl, (C₃ -C₁₈)cycloalkyl, (C₃ -C₁₈)cycloalkyl(C₁ -C₁₈)alkyl, (C₆-C₂₄)aryl, (C₇ -C₂₅)aralkyl, (C₂ -C₁₈)alkenyl, (C₈₋ C₂₆)aralkenyl, (C₂-C₁₈)-alkynyl, (C₈ -C₂₆)aralkynyl and heterocyclic, any of which may beoptionally substituted as defined below,

and R₈₀ is selected from the group consisting of R₈₁ as previouslydefined and a solubilising and/or protecting group Px which is labile invivo, then at least one of the following applies:

(i) R₅₀ is a group R₅₃, wherein R₅₃ is selected from the groupconsisting of C(D*)OR_(21*), C(D*)NR_(21*) R_(22*), C(D*)SR_(21*),C(D*)R₅₅, CF₃, R₅₅ and a solubilising group Px which is labile in vivo,wherein

D* has the meaning of D as previously defined,

R_(21*) and R_(22*) have the meaning of R₂₁ and R₂₂ respectively, aspreviously defined,

and wherein R₅₅ is selected from the group consisting of optionallysubstituted (C₁ -C₁₈)alkyl(C₆ -C₂₄)aryl, optionally substituted (C₂-C₁₈)alkenyl(C₆ -C₂₄)aryl, optionally substituted (C₂ -C₁₈)-alkynyl(C₆-C₂₄)aryl, optionally substituted (C₃ -C₁₈)cycloalkyl-(C₂ -C₁₈)alkenyl,optionally substituted (C₃ -C₁₈)cyclo-alkyl(C₂ -C₁₈)alkynyl, optionallysubstituted (C₃ -C₁₈)cycloalkyl -(C₆ -C₂₄)aryl, optionally substitutedacyl(C₆ -C₂₄)aryl, optionally. substituted heterocyclic(C₁ -C₁₈)allyl,optionally substituted heterocyclic(C₂ -C₁₈)alkenyl, optionallysubstituted heterocyclic-(C₂ -C₁₈)alkynyl and optionally substitutedheterocyclic(C₂ -C₁₈)-(C₆ -C₂₄)aryl,

and n', m', R_(1*), R₁₀, A', A'*, R₅₁ and R_(2*) are as previouslydefined,

(ii) one of R_(2*) and R₅, is a group R₅₄, wherein R₅₄ is selected fromthe group consisting of R_(55*), C(D*)NR_(21*) R_(22*), C(D*)OR_(55*),C(D*)R_(55*), C(D*)SR_(21*), CF₃, S(O)_(z) OR₁₂₀, S(O)_(z) NR₁₂₀ R₁₂₁,and a solubilising group Px which is labile in vivo, wherein z is 1 or 2and R₁₂₀ and R₁₂₁ are as previously defined or R₁₂₀ and R₁₂₁ togetherform a saturated or unsaturated cyclic, bicyclic or fused ring system asdefined below, and wherein R_(21*) and R_(22*) have the meaning of R₂₁and R₂₂ respectively, as previously defined, and R_(55*) has the meaningof R₅₅, as previously defined, and n', m', R_(1*), R₁₀, A', A'*, R₅₀ andthe other of R_(2*) and R₅₁ are as previously defined,

(iii) at least one A'or A'* is selected from the group consisting ofCR₁₂ R₁₃, CR₁₂ R₁₁₃, CR₁₁₂ R_(13*) and CR_(12*) R₁₁₃, wherein R₁₁₂ andR₁₁₃ are independently selected from the group consisting of R₅₅ aspreviously defined, C(D)OR_(21*), C(D)SR_(21*), C(D)NR_(21*) R_(22*), F,Cl, Br and I, wherein R_(21*) and R_(22*) have the meaning of R₂₁ andR₂₂ respectively, as previously defined,

and D, n', m', R_(1*), R_(2*), R₁₀, R₁₁, R₁₂, R_(12*), R₁₃, R_(13*), R₅₀and R₅₁ are as previously defined,

(iv) R₁, is selected from the group consisting of optionally substituted(C₂ -C₁₈)alkenyl, optionally substituted (C₂ -C₁₈)alkynyl, optionallysubstituted (C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkenyl, optionally substituted(C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkynyl, optionally substituted (C₆-C₂₄)aryl-(C₂ -C₁₈)alkenyl, optionally substituted (C₆ -C₂₄)aryl(C₂-C₁₈)alkynyl, optionally substituted (C₂ -C₁₈)acyl, wherein the optionalsubstituent is other than amino, optionally substituted (C₆ -C₂₄)aryl(C₂-C₁₈)acyl, optionally substituted heterocyclic(C₁ -C₁₈)alkyl, optionallysubstituted heterocyclic(C₂ -C₁₈)alkenyl, optionally substitutedheterocyclic(C₂ -C₁₈)alkynyl, C(O)OR₉₀, C(O)NR₉₁ R₉₂, CF₃, S(O)_(z)OR₁₂₀, S(O)_(z) NR₁₂₀ R₁₂₁ and a solubilising group Px which is labilein vivo,

wherein z is 1 or 2 and R₁₂₀ and R₁₂₁ are as previously defined,

wherein R₉₀ is selected from the group consisting of (C₃-C₁₈)cycloalkyl, (C₃ -C₁₈)cycloalkyl(C₁ -C₁₈)alkyl, heterocyclic, (C₁-C₁₈)alkyl-heterocyclic, (C₆ -C₂₄)aryl, (C₆ -C₂₄)aryl(C₁ -C₁₈)alkyl and

(C₆ -C₂₄)aryl(C₁ -C₁₈)alkylheterocyclic, and wherein R₉₁ and R₉₂ areindependently selected from the group consisting of optionallysubstituted (C₂ -C₁₈)alkenyl, optionally substituted (C₂ -C₁₈)alkynyl,optionally substituted (C₃ -C₁₈)cycloalkyl, optionally substituted (C₃-C₁₈)cycloalkyl-(C₁ -C₁₈)alkyl, optionally substituted (C₃-C₁₈)cycloalkyl-(C₂ -C₁₈)alkenyl, optionally substituted (C₃-C₁₈)cycloalkyl-(C₂ -C₁₈)alkynyl, optionally substituted (C₆-C₂₄)aryl-(C₂ -C₁₈)alkenyl, optionally substituted (C₆ -C₂₄)aryl-(C₂-C₁₈)alkynyl, optionally substituted (C₂ -C₁₈)acyl, optionallysubstituted (C₆ -C₂₄)aryl(C₂ -C₁₈)acyl, optionally substitutedheterocyclic, optionally substituted heterocyclic(C₁ -C₁₈)alkyl,optionally substituted heterocyclic(C₂ -C₁₈)alkenyl, and optionallysubstituted heterocyclic(C₂ -C₁₈)alkynyl, or R₉₁ and R₉₂ together form asaturated or unsaturated cyclic, bicyclic or fused ring system asdefined below,

and m', n', A', A'*, R₂ *, R₅₀, R₅₁ and R₁₀ are as previously defined,

(v) a group selected from R₁, R_(1*), R₂, R_(2*), R₉, R₁₁, R₁₂, R₅₀ andR₅₁, taken together with another group selected from R₁, R_(1*), R₂,R_(2*), R_(9*), R₁₀, R₁₁, R₁₂, R₅₀ and R₅₁ is selected from the groupconsisting of --C(O)-- and optionally substituted methylene;

(b) when W' is R_(1*) X* wherein X* is NR₁₀, and V' is Y* wherein Y* is##STR16## and B' is selected from --CH(OH)-- and --C(O)-- then at leastone of the following also applies when one of the conditions (i) to (iv)defined above in (a) applies:

(vi) n'>1,

(vii) n'=0,

(viii) m'>1,

(ix) m'=0,

(x) R₅₀ and R₅₁ together form part of a saturated or unsaturated cyclic,bicyclic or fused ring system as defined below,

(xi) R₅₀ is a group R₅₆, wherein R₅₆ is selected from the groupconsisting of C(D*)OR_(21*), C(D*)NR_(21*) R_(22*), C(D*)SR_(21*),C(D*)R₅₅ and a solubilising and/or protecting group Px which is labilein vivo, wherein R_(21*) and R_(22*) are as previously defined, and

(xii) n'=m'=1 and A'* is other than --CH₂ --, and (c) when B' isselected from ##STR17## and ##STR18## wherein R₁₄, R_(14*) and R₁₇ areas previously defined, then at least one group selected from R₂ orR_(2*), R₁₁, R₁₂, R₅₀ and R₅₁ together with another group selected fromR₁, or R_(1*), R₁₀, R₁₁ and R₁₂ forms a saturated or unsaturated cyclic,bicyclic or fused ring system as defined below, said ring beingsubstituted with at least one polar group selected from ═O, ═S, OH, SH,NHR_(10*) and C(O)OH, wherein R_(10*) has the meaning of R₁₀ aspreviously defined, said polar group being sterically capable of beinglocated within the compound of formula (I) not more than 5 ångstromunits from the P, O, S, N or C atom of group B,

provided that when W' is R_(1*) X* and X* is NH and V' is Y* wherein Y*is ##STR19## wherein R_(1*) is other than H and R₇₁ and R₇₂ areindependently selected from the group consisting of H, (C₁ -C₆)alkyl,optionally substituted phenyl, optionally substituted naphthyl,optionally substituted phenyl(C₁ -C₂)alkyl and optionally substitutednaphthyl-(C₁ -C₂)alkyl, and when

(a) B' is --CH(OH)-- and (A'), is --CH(R₇₃)--wherein R₇₃ is selectedfrom the group consisting of (C₁ -C₆)alkyl optionally substituted with1-5 fluorine atoms, (C₃ -C₆)alkenyl, (C₁ -C₆)alkoxy-CH₂ -, (CH₂)_(p)phenyl, (CH₂)_(p) naphthyl, (CH₂)_(p) -(C₅ -C₆)cycloalkyl and (CH₂)_(p)indolyl, wherein said (CH₂)_(n) phenyl, (CH₂)_(n) naphthyl, (CH₂)_(n)(C₅ -C₆)cycloalkyl and (CH₂)_(n) indolyl are optionally substituted withnitro, halogen, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy or (C₁ -C₄)alkylthio andwherein p is 0, 1 or 2, then (A'*)_(m') is other than ##STR20## whereinR₇₄ has the meaning of R₇₃ as previously defined, and when

(b) B' is ##STR21## wherein R₇₄ has the meaning of R₇₃ as previouslydefined and (A')_(n') is ##STR22## wherein R₇₃ is as previously defined,then (A'*)_(m) ' is other than --C(O)--, and when

(c) B' is --C(O)-- and (A')_(n') is ##STR23## wherein R₇₃ is aspreviously defined, then m' is other than 0.

As used herein, the term "(C₁ -C₁₈)alkyl" includes within its meaningstraight and branched chain alkyl groups having from 1 to 18 carbonatoms. Examples of such groups are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl,1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl,5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl,4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,4-dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl,1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl,1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnonyl, 1-,2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl,1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5, 6-or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-,9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-,2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1- or2-pentylheptyl, tridecyl, tetradecyl, hexadecyl, octadecyl and the like.

Typically an alkyl group is (C_(a) -C_(b))alkyl, in which a is selectedfrom a value presented in the column headed "a" in Table A below at oneof entries 1-17, and b has one of the values presented in the columnheaded "b" at that entry.

                  TABLE A    ______________________________________    Entry a       b    ______________________________________    1     1       2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18    2     2       3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18    3     3       4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18    4     4       5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18    5     5       6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18    6     6       7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18    7     7       8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18    8     8       9, 10, 11, 12, 13, 14, 15, 16, 17, 18    9     9       10, 11, 12, 13, 14, 15, 16, 17, 18    10    10      11, 12, 13, 14, 15, 16, 17, 18    11    11      12, 13, 14, 15, 16, 17, 18    12    12      13, 14, 15, 16, 17, 18    13    13      14, 15, 16, 17, 18    14    14      15, 16, 17, 18    15    15      16, 17, 18    16    16      17, 18    17    17      18    ______________________________________

As used herein, the term "(C₂ -C₁₈)alkenyl" includes within its meaningethylenically mono-, di- or poly-unsaturated alkyl groups having from 2to 18 carbon atoms, and may be straight-chain or branched. Examples ofsuch alkenyl groups are vinyl allyl, 1-methylvinyl, 1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1,3-pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl, 3-methyl-2-butenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl,2-methylpentenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1,3-octadienyl,1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1-undecenyl,oleyl, linoleyl and linolenyl.

Typically an alkenyl group is (C_(a) -C_(b))alkenyl, in which a isselected from a value presented in the column headed "a" in Table Aabove at one of entries 2-17, and b has one of the values presented inthe column headed "b" at that entry.

As used herein, the term "(C₂ -C₁₈)alkynyl" includes within its meaningmono-, di- and poly-acetylenically unsaturated alkyl groups having from2 to 18 carbon atoms, and may be straight-chain or branched. Examples ofsuch alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl,3-methyl-1-butynyl, n-hexynyl, methyl-pentynyl and (C₇ -C₁₂)alkynyl.

Typically an alkynyl group is (C_(a) -C_(b))alkynyl, in which a isselected from a value presented in the column headed "a" in Table Aabove at one of entries 2-17, and b has one of the values presented inthe column headed "b" at that entry.

As used herein, the term "(C₃ -C₁₈)cycloalkyl" refers to otionallyunsaturated mono-, di- or polycyclic alkyl groups having from 3 to 18carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,cyclooctatrienyl, cyclooctatetraenyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, (C₉ -C₁₂)cycloalkynyl, bicyclo2.2.1!heptanyl, bicyclo 2.2.1!heptenyl, bicyclo 2.2.1!-heptadienyl,bicyclo 2.2.2!octanyl, bicyclo 2.2.2!octenyl, bicyclo 3.3.1!nonyl,bicyclo- 3.1.0.!hexyl, bicyclo 4.1.0!heptyl, bicyclo 3.2.1.!octyl,bicyclo 3 .3.0!octyl, bicyclo- 3.3.0!octenyl, bicyclo 3.3.1!nonyl,bicyclo 4.4.0!decyl, adamantyl, tricyclo 5.2.1.0²,6 !decyl and the like.

Typically a cycloalkyl group is (C_(a) -C_(b))cycloalkyl, in which a isselected from a value presented in the column headed "a" in Table Aabove at one of entries 3-17, and b has one of the values presented inthe column headed "b" at that entry.

As used herein, the term "(C₃ -C₁₈)cycloalkyl(C₁ -C₁₈)allyl" refers to a(C₁ -C₁₈)alkyl group as defined above, substituted with a (C₃-C₁₈)cycloalkyl group as defined above. Examples of cycloalkylalkylgroups include cycloalkyl-loweralkyl groups, such as cycloalkylmethyl,cycloalkylethyl, cycloalkylpropyl, cycloalkylbutyl, cycloalkylisopropyl,cycloalkylisobutyl, cycloalkylpentyl and cycloalkylhexyl, wherein thecycloalkyl is as exemplified in the preceding paragraph.

As used herein, the term "(C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkenyl" refers toa (C₂ -C₁₈)alkenyl group as defined above, substituted with a (C₃-C₁₈)cycloalkyl group as defined above. Examples of cycloalkylalkenylgroups include cycloalkyl-loweralkenyl groups, such ascycloalkylethenyl, cycloalkylpropenyl, cycloalkylbutenyl,cycloalkylisobutenyl, cycloalkylpentenyl and cycloalkylhexenyl, whereinthe cycloalkyl is as exemplified above under "(C₃ -C₁₈)cycloalkyl".

As used herein, the term "(C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkynyl" refers toa (C₂ -C₁₈)alkynyl group as defined above, substituted with a (C₃-C₁₈)cycloalkyl group as defined above. Examples of cycloalkylalkynylgroups include cycloalkyl-loweralkynyl groups, such ascycloalkylethynyl, cycloalkylpropynyl, cycloalkylbutynyl,cycloalkylpentynyl and cycloalkylhexynyl, wherein the cycloalkyl is asexemplified above under "(C₃ -C₁₈)cycloalkyl".

As used herein, the term "(C₆ -C₂₄)aryl" refers to single, polynuclear,conjugated and fused residues of aromatic hydrocarbons having from 6 to24 carbon atoms. Examples of such groups are phenyl, biphenyl,terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, acenaphthyl,anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl,phenanthrenyl, fluorenyl, pyrenyl, indenyl, indanyl, azulenyl, chrysenyland the like. In all cases, any available position of the fused orconjugated bicyclic system can be used for attachment to the remainderof the molecule of formula (I).

Typically an aryl group is (C_(a) -C_(b))aryl, in which a is selectedfrom a value presented in the column headed "a" in Table B below at oneof entries 1-18, and b has one of the values presented in the columnheaded "b" at that entry.

                  TABLE B    ______________________________________    Entry a       b    ______________________________________    1     6       10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24    2     10      12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24    3     12      13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24    8     13      14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24    9     14      15, 16, 17, 18, 19, 20, 21, 22, 23, 24    10    15      16, 17, 18, 19, 20, 21, 22, 23, 24    11    16      17, 18, 19, 20, 21, 22, 23, 24    12    17      18, 19, 20, 21, 22, 23, 24    13    18      19, 20, 21, 22, 23, 24    14    19      20, 21, 22, 23, 24    15    20      21, 22, 23, 24    16    21      22, 23, 24    17    22      23, 24    18    23      24    ______________________________________

As used herein, the term "(C₆ -C₂₄)aryl(C₁ -C₁₈)alkyl" refers to a (C₁-C₁₈)alkyl substituted with one or more (C₆ -C₂₄)aryl groups aspreviously defined. Examples of such groups are aryl-loweralkyl groupssuch as arylmethyl, arylethyl, arylisopropyl, arylpropyl, arylbutyl,arylisobutyl, arylpentyl and arylhexyl, wherein the aryl is asexemplified in the preceding paragraph, such as benzyl, diphenylmethyl,2-phenylethyl, 1-phenylethyl, naphthylmethyl, 3-phenylpropyl,triphenylmethyl, 1,3-diphenylpropyl, 2- or 3-β-naphthylpropyl,2-benzyl-propyl and the like.

As used herein, the term "(C₇ -C₂₅)aralkyl" refers to an alkyl groupsubstituted with an aryl group, wherein the total number of carbon atomsin the aryl-substituted alkyl group is from 7 to 25. Optionalsubstituents for (C₇ -C₂₅)aralkyl are as defined below with respect to(C₆ -C₂₄)aryl(C₁ -C₁₈)alkyl.

As used herein, the term "(C₆ -C₂₄)aryl(C₁ -C₁₈)alkenyl" refers to aalkenyl group substituted with one or more (C₆ -C₂₄)aryl groups aspreviously defined. Examples of such groups are aryl-loweralkenyl groupssuch as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl,arylpentenyl and arylhexenyl, wherein the aryl is as exemplified aboveunder "(C₆ -C₂₄)aryl" such as styryl, cinnamyl, 2-naphthylethenyl,1phenyl-2-methyl-1-propenyl, 2-phenyl-2-butenyl and the like.

As used herein, the term "(C₈ -C₂₆)aralkenyl" refers to an alkenyl groupsubstituted with an aryl group, wherein the total number of carbon atomsin the aryl-substituted alkenyl group is from 8 to 26. Optionalsubstituents for (C₈ -C₂₆)aralkenyl are as defined below with respect to(C₆ -C₂₄)aryl(C₂ -C₁₈)alkenyl.

As used herein, the term "(C₆ -C₂₄)aryl(C₁ -C₁₈)alkynyl" refers to aalkynyl group substituted with one or more (C₆ -C₂₄)aryl groups aspreviously defined. Examples of such groups are aryl-loweralkenyl groupssuch as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl,arylpentenyl and arylhexenyl, wherein the aryl is as exemplified aboveunder "(C₆ -C₂₄)aryl" such as phenylethynyl and the like.

As used herein, the term "(C₈ -C₂₆)aralkynyl" refers to an alkynyl groupsubstituted with an aryl group, wherein the total number of carbon atomsin the aryl-substituted alkynyl group is from 8 to 26. Optionalsubstituents for (C₈ -C₂₆)aralkynyl are as defined below with respect to(C₆ -C₂₄)aryl(C₂ -C₁₈)alkynyl.

As used herein, the term "(C₁ -C₁₈)acyl" refers to a group R₃₀₀ C(O)--or R₃₀₀ C(S)--, wherein R₃₀₀ is selected from the group consisting ofhydrogen, (C₁ -C₁₈)alkyl, (C₂ -C₁₈)alkenyl, (C₂ -C₁₈)alkynyl, (C₃-C₁₈)cycloalkyl (C₃ -C₁₈)cycloalkyl-(C₁ -C₁₈)alkyl, (C₃-C₁₈)cycloalkyl(C₂ -C₁₈)alkenyl, (C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkynyl,(C₆ -C₂₄)aryl, (C₆ -C₂₄)aryl(C₁ -C₁₈)alkyl, (C₆ -C₂₄)aryl(C₂-C₁₈)alkenyl, (C₆ -C₂₄)aryl-(C₂ -C₁₈)alkynyl, heterocyclic,heterocyclic(C₁ -C₁₈)alkyl, heterocyclic(C₂ -C₁₈)alkenyl, andheterocyclic(C₂ -C₁₈)alkynyl.

Typically an acyl group is (C_(a) -C_(b))acyl, in which a is selectedfrom a value presented in the column headed "a" in Table A above at oneof entries 1-17, and b has one of the values presented in the columnheaded "b" at that entry.

Examples of acyl groups include loweralkylcarbonyl such as formyl,acetyl, propionyl, butyryl; loweralkenylcarbonyl such as pivaloyl,acryloyl, vinylacetyl, crotonoyl, 3-pentenoyl, 4-pentenoyl; andloweralkynylcarbonyl such as propioloyl, 2-butynoyl and 3-butynoyl, anyof which may be substituted with cycloalkyl, aryl or heterocyclic asexemplified herein, as, for example, cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, 1-cyclopentenylcarbonyl,cyclopentylacetyl, 1-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl,cyclohexylacetyl, cyclohexenylacetyl, 1,4cyclohexadienylacetyl, bicyclo2.2.1!hept-2-ylcarbonyl, bicyclo- 2.2.1!heptylacetyl, bicyclo2.2.1!hepten-2-ylcarbonyl, bicyclo 2.2.2!oct-2-ylcarbonyl, bicyclo2.2.2!octylacetyl, bicyclo 2.2.2!octyl-3-propionyl, bicyclo2.2.2!octen-2-yl-carbonyl, bicyclo 3.3.1!non-9-ylcarbonyl, bicyclo3.3.1!non-9-ylacetyl, bicyclononyl-3-propionyl, bicyclo4.4.0!dec-2-ylcarbonyl, bicyclo 4.4.0!dec-2-ylacetyl,1-adamantylcarbonyl, 2-adamantylcarbonyl, 1-adamantylacetyl,2-adamantylacetyl, tricyclo 5.2.1.0²,6 !dec-8-ylacetyl, benzoyl,phenylacetyl, diphenylacetyl, triphenylacetyl, 3-phenylpropionyl,dibenzylacetyl, α-naphthoyl, β-naphthoyl, α-naphthylacetyl,β-naphthylacetyl, indenylcarbonyl, indanylcarbonyl,phenanthrenylcarbonyl, 9-fluorenylcarbonyl, pyrrolylcarbonyl,pyrrolylacetyl, furylcarbonyl, furylacetyl, thienylcarbonyl,thienylacetyl, pyrazinylcarbonyl, pyrazinylacetyl, pyrrolidinylcarbonyl,pyrrolidinylacetyl, pyridylcarbonyl, pyridylacetyl, pyrimidinylcarbonyl,pyrimidinylacetyl, piperidylcarbonyl, piperidylacetyl,piperazinylcarbonyl, piperazinylacetyl, morpholinylcarbonyl,morpholinylacetyl, thiomorpholinylcarbonyl, thiomorpholinylacetyl,indolylcarbonyl, indolylacetyl, quinolylcarbonyl, quinolylacetyl,isoquinolylcarbonyl, isoquinolylacetyl, quinoxalinylcarbonyl,benzofuranylcarbonyl, benzofuranylacetyl, indolinylcarbonyl,indolinylacetyl, 1,2,3,4-tetrahydroquinolylcarbonyl,1,2,3,4-tetrahydroquinolylacetyl, 1,2,3,4-tetrahydroisoquinolylcarbonyl,1,2,3,4-tetrahydroisoquinolylacetyl, cyclohexylacryloyl, cinnamoyl,styrylacetyl and phenylpropioloyl.

As used herein, the term "heterocyclic" refers to any saturated orunsaturated 3- to 16-membered monocyclic, bicyclic or polycyclic ringcontaining one or more heteroatom independently selected from oxygen,nitrogen and sulphur. The term "heterocyclic" includes any group inwhich a heterocyclic ring is fused to one or more benzene, naphthaleneor cycloalkane rings. Sulfur-containing heterocyclics may be substitutedat sulfur with one or two oxygen atoms. Examples of heterocyclics arepyridyl, thienyl, furyl, pyrrolyl, indolyl, pyridazinyl,perhydropyridazinyl, pyrazolyl, pyrazoldinyl,2,3,5,6-tetrahydropyrazinyl, phthalazinyl,1,2,3,4-tetrahydrophthalazinyl, perhydrophthalazinyl, thiazolyl,pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl,purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl,benzothiazolyl, piperidyl, tetrahydrofuryl, imidazolyl, oxazolyl,thiazolidino, oxazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl,imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolinyl, benzothienyl,benzisoxazolyl, benzoisothiazolyl, benzothiadiazolyl, tetrazolyl,triazolyl, thiadiazolyl, benzimidazolyl, pyrrolinyl, quinuclidinyl,1,4-thioxanyl, 1,3-thioxanyl, azanorbornyl, isoquinuclidinyl, pyranyl,furazanyl, azepinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl,quinoxalinyl, cinnolyl, 1,2,3,4-tetrahydrocinnolinyl, pteridinyl,naphthyridinyl, 4H-quinolizinyl, benz e!indolyl, benzoxazinyl,benzoxadiazolyl, benzothiazinyl, benzotriazolyl, carbazolyl,β-carbolinyl, 1,2,3,4,5,6-hexahydro-β-carbolinyl, phenanthridyl,phenoxazinyl, phenothiazinyl, 1-azaacenaphthenyl, thiatriazolyl,oxadiazolyl, thiadiazolyl, chromanyl, thiachromanyl, isochromanyl,chromenyl, cyclohexa b!pyrrolyl, cyclohepta b!pyrrolyl, cyclohexad!pyrazolyl, cyclohexa b!pyridyl, cyclohexa b!pyrazinyl, cyclohexab!pyrimidinyl, cyclohexa b!-1,4-oxazinyl, cyclohexa b!-1,4-thiazinyl,2-imidazolinyl, 2,3-dihydropyridyl, piperazinyl, thiomorpholinyl,S,S-dioxo-thiomorpholinyl, indolinyl, S,S-dioxo-1,2,3-benzothiadiazolyl,S,S-dioxo-1,2-thioxanyl, S,S-dioxo-1,4-thioxanyl, isoindolinyl,4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetra-hydroquinolyl,1,2,3,4-tetrahydroisoquinolyl, hexahydroquinolyl, hexahydroisoquinolyl,1,2,3,4-tetrahydro-3,1-benzodiazinyl, 3,4-dihydro-3H4,1-benzoxazinyl,3,4-dihydro-3H-4,1-benzothiazinyl,2,3,4,5-tetrahydro-1H-5,1-benzazepinyl and 5,6-dihydro-phenanthridinyland the like.

Configurations which result in unstable heterocyclics are not includedwithin the scope of the definition of "heterocyclic" or "saturated orunsaturated cyclic, bicyclic or fused ring system".

As used herein, the term "heterocyclic(C₁ -C₁₈)alkyl" refers to a (C₁-C₁₈)alkyl group as previously defined, which is substituted with aheterocyclic group as previously defied. Examples of such groups areheterocyclic-loweralkyl groups such as heterocyclicmethyl,heterocyclicethyl, heterocyclicisopropyl, heterocyclicpropyl,heterocyclicbutyl, heterocyclicisobutyl, heterocyclicpentyl andheterocyclichexyl, wherein the heterocyclic is as exemplified in thepreceding paragraph.

As used herein, the term "heterocyclic(C₁ -C₁₈)alkenyl" refers to a (C₁-C₁₈)alkenyl group as previously defined, which is substituted with aheterocyclic group as previously defined. Examples of such groups areheterocyclic-loweralkenyl groups such as heterocyclicethenyl,heterocyclicpropenyl, heterocyclicbutenyl, heterocyclicisobutenyl,heterocyclicpentenyl and heterocyclichexenyl, wherein the heterocyclicis as exemplified above under "heterocyclic".

As used herein, the term "heterocyclic(C₁ -C₁₈)alkynyl" refers to a (C₁-C₁₈)alkynyl group as previously defined, which is substituted with aheterocyclic group as previously defined.

As used herein, the term "alkylidene" refers to divalent radicalsderived from alkyl groups. Examples of such radicals are --CH₂ --, --CH₂CH₂ --, --CH═CH--, --CH₂ CH₂ CH₂ --, --C(═CH₂)CH₂ --, --CH₂ CH ═CH--,--(CH₂)₄ --, --CH₂ CH₂ CH ═CH--, --CH₂ CH═CHCH₂ -- and --(CH₂)r-- wherer is 5-12. The term also refers to such radicals in which one or more ofthe bonds of the radical from part of a cyclic system, and to suchradicals wherein one or more carbon atoms is replaced by O, S or NH.Examples of such radicals are groups of the structure ##STR24## andsimilar groups, including those shown above wherein any N or O atom isreplaced by S.

As used herein the term "saturated or unsaturated cyclic, bicyclic orfused ring system" refers to a stable cyclic system of up to 16 carbonatoms, wherein said ring system may contain: for 3- and 4-memberedrings, one heteroatom; for 5-membered rings, one or two heteroatoms; for6- and 7-membered rings, one to three heteroatoms; for 8- and 9-memberedrings, from one to four heteroatoms; for 10- and 11-membered rings, fromone to five heteroatoms; for 12- and 13-membered rings, from one to sixheteroatoms; for 14- and 15-membered rings, from one to sevenheteroatoms; and for 16-membered rings, from one to eight heteroatoms;the heteroatom(s) being independently selected from oxygen, nitrogen andsulphur; which ring system may be substituted with one or moresubstituents independently selected from: R₁₅₀ and a group T, where R₁₅₀has the meaning of R₂₀ as previously defined, and where T is selectedfrom the group consisting of --F, --Cl, --Br, --I, --CF₃, --CN, --NCO,--NCS, --OCN, --SCN, --N₃, --OR', --NR'", --NR'C(O)R", --NR'C(O)OR",--NR'C(O)NR"R", --NO₂, --SR', --S(O)R', --S(O)₂ R', --S(O)OR', --S(O)₂OR', --S(O)NR'R", --S(O)₂ NR'R", ═O, ═S, ═N₂, ═NOH, ═NOR', --NR"OR',--CHO, --OC(O)R', --OC(O)OR', --OC(O)NR'R", --C(O)R', --C(O)OR',--C(O)NR'R", --OC(S)R', --OC(S)OR', --OC(S)NR'R", --C(S)R', --C(S)OR',--C(S)NR'R", --SC(O)R', --SC(O)OR', --SC(O)NR'R", --C(O)SR', --SC(S)R',--SC(S)OR', --SC(S)NR'R", --C(S)SR', --C(═NR')OR", --C(=NR')SR",--C(═NR')NR"R"', --OS(O)R', --OS(O)₂ R', --OS(O)OR', --OS(O)₂ OR',--OS(O)NR'R", --OS(O)₂ NR'R", NR'S(O)2NR"R"', --NR'S(O)₂ R",--NHC(═NH)NR', --C(═NH)NR', --P(O)(OR')R", --P(O)(SR')R",--P(O)(OR')OR", --P(O)(OR')NR"R"', --P(O)R'R", --OP(O)(OR')R",--OP(O)(OR')OR", --OP(O)(SR')OR", --OP(O)(OR')NR"R"', --OP(O)R'R", and--B(OR')(OR"), wherein R', R" and R"' are independently selected fromthe group consisting of hydrogen, (C₁ -C₁₈)alkyl, typically (C₁-C₁₂)alkyl; (C₃ -C₁₈)cycloalkyl, typically (C₃ -C₁₂)cycloalkyl; (C₃-C₁₈)cycloalkyl(C₁ -C₁₈)alkyl, typically (C₃ -C₁₂)cycloalkyl(C₁-C₆)alkyl; (C₆ -C₂₄)aryl, typically (C₆ -C₆)aryl; (C₆ -C₂₄)aryl(C₁-C₁₈)alkyl, typically (C₆ -C₁₀)aryl(C₁ -C₆)alkyl; (C₂ -C₁₈)alkenyl,typically (C₂ -C₁₂)alkenyl; (C₆ -C₂₄)-aryl(C₂ -C₁₈)alkenyl, typically(C₆ -C₁₀)aryl(C₂ -C₆)alkenyl; (C₂ -C₁₈)alkynyl, typically (C₂-C₁₂)alkynyl; (C₆ -C₂₄)aryl(C₂ -C₁₈)aralkynyl, typically (C₆-C₁₀)aryl(C₁ -C₆)alkynyl, heterocyclic, heterocyclic(C₁ -C₁₈)alkyl,typically heterocyclic(C₁ -C₁₂)alkyl, heterocyclic-(C₂ -C₁₈)alkenyl,typically heterocyclic(C₂ -C₁₂)alkenyl and heterocyclic(C₂ -C₁₈)alkynyl,typically heterocyclic(C₂ -C₁₂)alkynyl, and wherein R', R" and R"' maybe optionally substituted with up to six groups independently selectedfrom hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)aryloxy, (C₁ -C₆)thioalkoxy, (C₁-C₆)thioaryloxy, (C₁ -C₆)alkoxy(C₁ -C₆)alkoxy, amino, (C₁-C₆)alkylamino, di(C₁ -C₆)alkylamino, fluoro, chloro, bromo, iodo,carboxy, (C₁ -C₆)alkoxycarbonyl, (C₁ -C₆)alkylaminocarbonyl and di(C₁-C₆)alkylaminocarbonyl. Examples of saturated or unsaturated cyclic,bicyclic or fused ring systems are the heterocyclic and cyclicalkylidene groups exemplified above.

As used herein, the term "optionally substituted (C₁ -C₁₈)alkyl" refersto a (C₁ -C₁₈)alkyl group as defined above wherein one or more hydrogenatoms are replaced by one or more substitutents T as previously defined.

Examples of substituted (C₁ -C₁₈)alkyl groups include hydroxy-loweralkylsuch as hydroxymethyl, hydroxyethyl and 3-hydroxypropyl;loweralkoxy-loweralkyl such as methoxymethyl, 2-methoxyethyl,2,2-dimethoxyethyl and 3-methoxypropyl; aryloxy-loweralkyl such asphenoxymethyl, phenoxyethyl, α-naphthyloxymethyl and β-naphthyloxyethyl;arylloweralkoxy-loweralkyl such as benzyloxymethyl, benzyloxyethyl and3-benzyloxypropyl; halo-loweralkyl such as chloromethyl,trifluoromethyl, 2-fluoro-, 2-chloro-, 2-bromo- or 2-iodo-ethyl,2,2,2-trifluoro-ethyl, 2,2,2-trichloro-ethyl, 3-chloropropyl and3-bromopropyl; amino-loweralkyl such as aminomethyl, 2-aminoethyl,3-aminopropyl, 5-aminopentyl, dimethylaminomethyl, 2-dimethylaminoethyland 3-phenyl-aminopropyl; carboxy-loweralkyl such as carboxymethyl,carboxyethyl and 3-carboxypropyl; acylloweralkyl such as acylmethyl,acylethyl, acylpropyl, acylisopropyl, acylbutyl, acylisobutyl,acylpentyl and acylhexyl wherein the acyl is as exemplified above under"(C₁ -C₁₈)acyl"; acyloxy-loweralkyl such as acetoxymethyl, acetoxyethyl,2-acetoxypropyl, 3-acetoxypropyl, propionyloxyethyl and3-propionyloxypropyl; loweralkylcarbonylamino-loweralkyl such asacetylaminomethyl, acetylaminoethyl, 2-acetylaminopropyl,propionylaminomethyl and propionylaminoethyl;loweralkylaminocarbonylamino-loweralkyl, such asdimethylaminocarbonylaminoethyl; sulfonyl-loweralkyl such asmethylsulfonyl-methyl, ethylsulfonyl-methyl, tert-butylsulfonyl-methyl,phenylsulfonylmethyl, phenylsulfonylethyl, 4-toluenesulfonylethyl and4-toluenesulfonylmethyl; cyano-loweralkyl such as cyanomethyl,2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 2-cyanobutyl, 3-cyanobutyland 4-cyanobutyl; oxo-lowerallyl such as 2-oxo-propyl, 2-oxo-butyl,3-oxo-butyl, 2-, 3- or 4-oxo-pentyl and 2,4-dioxo-pentyl; andlower-alkyl groups substituted with two or more than differentsubstitutents as exemplified above.

As used herein, the term "optionally substituted (C₁ -C₁₈)alkenyl"refers to a (C₁ -C₁₈)alkenyl group as defined above wherein one or morehydrogen atoms are replaced by a substituent or substitutents T aspreviously defined.

As used herein, the term "optionally substituted (C₁ -C₁₈)alkynyl"refers to a (C₁ -C₁₈)alkynyl group as defined above wherein one or morehydrogen atoms are replaced by a substituent or substitutents T aspreviously defined.

As used herein, the term "optionally substituted (C₃ -C₂₄)cycloalkyl"refers to a (C₃ -C₂₄)cycloalkyl group as defined above wherein one ormore hydrogen atoms are replaced by a substituent or substitutentsindependently selected from RIV and T as previously defined, whereinR^(IV) is selected from (C₁ -C₁₈)alkyl, (C₂ -C₁₈)alkenyl, (C₂-C₁₈)alkynyl, (C₃ -C₁₈)cycloalkyl, (C₃ -C₁₈)cycloalkyl(C₁ -C₁₈)alkyl,(C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkenyl, (C₃ -C₁₈)cycloalkyl(C₂-C₁₈)alkynyl, (C₂ -C₁₈)acyl, (C₆ -C₂₄)aryl(C₂ -C₁₈)acyl, heterocyclic,heterocyclic(C₁ -C₁₈)alkyl, heterocyclic(C₂ -C₁₈)alkenyl, andheterocyclic(C₂ -C₁₈)alkynyl, and wherein R^(IV) may be substituted withup to six groups independently selected from hydroxy, amino, (C₁-C₆)alkoxy, (C₁ -C₆)alkoxy(C₁ -C₆)alkoxy, amino, (C₁ -C₆)alkylamino,di(C₁ -C₆)alkylamino, fluoro, chloro, bromo, iodo, carboxy, (C₁-C₆)alkoxycarbonyl, (C₁ -C₆)alkylaminocarbonyl and di(C₁-C₆)alkylaminocarbonyl.

As used herein, the term "optionally substituted (C₃ -C₂₄)cyclo-alkyl(C₁-C₁₈)alkenyl" refers to a (C₃ -C₂₄)cycloalkyl(C₁ -C₁₈)alkenyl group asdefined above which are substituted in the cycloalkyl group by asubstituent or substitutents independently selected from thesubstituents defined above for (C₃ -C₂₄)cycloalkyl, and/or substitutedin the alkenyl group by one or more substituents T as previouslydefined.

As used herein, the term "optionally substituted (C₃ -C₂₄)cyclo-alkyl(C₁-C₁₈)alkynyl" refers to a (C₃ -C₂₄)cycloalkyl(C₁ -C₁₈)alkynyl group asdefined above which are substituted in the cycloalkyl group by asubstituent or substitutents independently selected from thesubstituents defined above for (C₃ -C₂₄)cycloalkyl, and/or substitutedin the alkynyl group by one or more substituents T as previouslydefined.

As used herein, the term "optionally substituted (C₆ -C₂₄)aryl" refersto a (C₆ -C₂₄)aryl group as defined above wherein one or more hydrogenatoms are replaced by a substituent or substitutents independentlyselected from R^(V) and T*, wherein T* is selected from the groupconsisting of --F, --Cl, --Br, --I, --CF₃, --CN, --NCO, --NCS, --OCN,--SCN, --N₃, --OR', --NR'R", --NR'C(O)R", --NR'C(O)OR", --NR'C(O)NR"R"',--NO₂, --SR', --S(O)R', --S(O)₂ R', --S(O)OR', --S(O)₂ OR', --S(O)NR'R",--S(O)₂ NR'R", --NR" OR', --CHO, --OC(O)R', --OC(O)OR', --OC(O)NR'R",--C(O)R', --C(O)OR', --C(O)NR'R", --OC(S)R', --OC(S)OR', --OC(S)NR'R",--C(S)R', --C(S)OR', --C(S)NR'R", --SC(O)R', --SC(O)OR', --SC(O)NR'R",--C(O)SR', --SC(S)R', --SC(S)OR', --SC(S)NR'R", --C(S)SR', --C(═NR')OR", --C(═NR')SR", --C(═NR')NR"R"', --OS(O)R', --OS(O)₂ R',--OS(O)OR', --OS(O)₂ OR', --OS(O)NR'R", --OS(O)₂ NR'R", NR'S(O)₂ NR"R"',NR'S(O)₂ R", --NHC(═NH)NR', --C(═NH)NR', --OP(O)(OR')R",--OP(O)(OR')OR", --OP(O)(SR')OR", --OP(O)(OR')NR"R"', --OP(O)R'R", and--B(OR')(OR"), wherein R', R" and R"'are as defined above with respectto the substituent T; and wherein RV is selected from (C₁ -C₁₈)alkyl,(C₂ -C₁₈)alkenyl, (C₂ -C₁₈)alkynyl, (C₃ -C₁₈)cycloalkyl, (C₃-C₁₈)cycloalkyl(C₁ -C₁₈)alkyl, (C₃ -C₁₈)cycloalkyl(C₂ -C₁₈)alkenyl, (C₃-C₁₈)cycloalkyl-(C₂ -C₁₈)alkynyl, (C₂ -C₁₈)acyl, (C₆ -C₂₄)aryl(C₂-C₁₈)acyl, heterocyclic, heterocyclic-(C₁ -C₁₈)alkyl, heterocyclic(C₂-C₁₈)alkenyl, and heterocyclic(C₂ -C₁₈)alkynyl, and wherein RV may besubstituted with up to six groups independently selected from hydroxy,amino, (C₁ -C₆)alkoxy, (C₁ -C₆)aryloxy, (C₁ -C₆)thioalkoxy, (C₁-C₆)thioaryloxy, (C₁ -C₆)alkoxy(C₁ -C₆)alkoxy, amino, (C₁-C₆)alkylamino, di(C₁ -C₆)alkylamino, fluoro, chloro, bromo, iodo,carboxy, (C₁ -C₆)alkoxycarbonyl, (C₁ -C₆)alkylaminocarbonyl and di(C₁-C₆)alkylaminocarbonyl. The term "optionally substituted (C₆ -C₂₄)aryl"includes mono-, di- and polysubstituted (C₆ -C₂₄)aryl groups. Examplesof substituted aryl groups are loweralkyl-aryl, loweralkenyl-aryl, arylloweralkyl-arylloweralkylcarbonyl-aryl, heterocyclic-aryl andheterocyclicloweralkyl-aryl wherein the aryl group is as exemplifiedabove; halo-aryl such as 4-chlorophenyl, 2,4-dichlorophenyl,1-chloro-2-naphthyl and 4-chloro-l-naphthyl; hydroxy-aryl such as2-hydroxyphenyl, 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl,2-hydroxy-8-naphthyl, 3,4,5-trihydroxyphenyl and 2,4,5-trihydroxyphenyl;loweralkoxyaryl such as 4-methoxyphenyl, 3,4-dimethoxyphenyl,2,4-dimethoxyphenyl and 1-methoxy-2-naphthyl; carboxyaryl such as2-carboxy-phenyl, 2-carboxy-l-naphthyl, 1-carboxy-2-naphthyl and9-carboxy-2-anthracyl; acylaryl, wherein the acyl group is as exemplifedabove under "(C₁ -C₁₈) acyl", such as 4-formylphenyl, 4-acetylphenyl,2-benzoylphenyl, 2-methoxycarbonyl-phenyl, 2-ethoxycarbonyl-1-naphthyl,1-methoxycarbonyl-2-naphthyl, 9-methoxycarbonyl-2-anthracyl,2-carbamoyl-phenyl, 2-carbamoyl-1-naphthyl, 1-carbamoyl-2-naphthyl,4-dimethylaminocarbonyl-phenyl, ⁴ -morpholinocarbonylphenyl,4-(2-pyridylmethoxy)carbonyl-phenyl and 4-benzyloxycarbonyl-phenyl;nitro-aryl such as 4-nitrophenyl and 2,4-dinitrophenyl; amino- or(substituted amino)-aryl such as 4-aminophenyl, 2,4-diaminophenyl,4-dimethylaminophenyl, 4-anilinophenyl, 2-(2,6-dichloroanilino)-phenyl,2,4-di-(benzyloxycarbonylamino)-phenyl and4-(2-quinolinecarbonylamino)-phenyl; and cyano-aryl such as4-cyanophenyl, as well as aryl groups substituted with two or more ofthe substituents exemplified above.

As used herein, the term "optionally substituted (C₆ -C₂₄)aryl(C₁-C₁₈)alkyl" refers to a (C₆ -C₂₄)aryl(C₁ -C₁₈)alkyl group as previouslydefined substituted in the aryl group with one or more substitutentsdefined above for (C₆ -C₂₄)aryl and/or substituted in the alkyl groupwith one or more substitutents defined above for (C₁ -C₁₈)alkyl.Examples of such groups are (substituted aryl)-lower-alkyl such as(substituted aryl)methyl, (substituted aryl)ethyl, (substitutedaryl)propyl, (substituted aryl)iso-propyl, (substituted aryl)butyl,(substituted aryl)pentyl and (substituted aryl)hexyl, aryl(substitutedloweralkyl) such as phenyl(substituted loweralkyl), naphthyl(substitutedloweralkyl), biphenyl(substituted loweralkyl),tetrahydronaphthyl(substituted loweralkyl), indenyl-(substitutedloweralkyl) and indanyl(substituted loweralkyl), and (substitutedaryl)-(substituted loweralkyl), wherein in each case substituted aryl isas exemplified above with respect to "optionally substituted (C₆-C₂₄)aryl" and (substituted loweralkyl) is as exemplified above withrespect to "optionally substituted (C₁ -C₁₈)alkyl".

As used herein, the term "optionally substituted (C₆ -C₂₄)aryl(C₁-C₁₈)alkenyl" refers to a (C₆ -C₂₄)aryl(C₁ -C₁₈)alkenyl group aspreviously defined substituted in the aryl group with one or moresubstitutents defined above for (C₆ -C₂₄)aryl and/or substituted in thealkenyl group with one or more substitutents defined above for (C₁-C₁₈)alkyl.

As used herein, the term "optionally substituted (C₆ -C₂₄)aryl(C₁-C₁₈)alkynyl" refers to a (C₆ -C₂₄)aryl(C₁ -C₁₈)alkynyl group aspreviously defined substituted in the aryl group with one or moresubstitutents defined above for (C₆ -C₂₄)aryl and/or substituted in thealkynyl group with one or more substitutents defined above for (C₁-C₁₈)alkyl.

As used herein, the term "optionally substituted (C₁ -C₁₈)acyl" refersto a (C₁ -C₁₈)acyl group as previously defined which may be substitutedwith one or more groups selected from the substituents defined for (C₁-C₁₈)alkyl, and includes within its meaning an acyl residue of anaturally occurring or synthetic amino acid or azaamino acid, or an acylresidue of a peptide chain containing 24 naturally occurring orsynthetic amino acids and/or azaamino acids.

Examples of substituted acyl groups include acyl residues of any of thenaturally occurring or synthetic amino acids exemplified herein,hydroxyloweralkanoyl, loweralkoxyloweralkanoyl, acetylloweralkanoyl,cyanoloweralkanoyl, carboxyloweralkanoyl, hydroxycarboxyloweralkanoyl,fluoroloweralkanoyl, chloroloweralkanoyl, bromoloweralkanoyl,thioloweralkanoyl, loweralkanethioloweralkanoyl, aminoloweralkanoyl,loweralkylaminoloweralkanoyl, di-(loweralkylamino)loweralkanoyl,carbamoylloweralkanoyl, loweralkoxycarbonyl, carbamoyl,loweralkylaminocarbonyl and di-(loweralkylamino)-carbonyl, whereloweralkanoyl is an alkanoyl group of from 1 to 6 carbon atoms, forexample formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl andhexanoyl, and where loweralkyl signifies a (C₁ -C₆)alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, neo-pentyl and hexyl.

As used herein, the term "optionally substituted heterocyclic" refers toa heterocyclic group as previosly defined wherein one or more hydrogenatoms may be replaced with a group selected from the substitutentsdefined above with regard to optionally substituted (C₆ -C₂₄)aryl.Examples of substituted heterocyclic groups includeloweralkylheterocyclic, arylheterocyclic, aryloxyheterocyclic,loweralkoxyheterocyclic, oxo-heterocyclic, hydroxyheterocyclic,loweralkoxycarbonylheterocyclic and loweralkanoylheterocyclic.

As used herein, the term "optionally substituted heterocyclic(C₁-C₁₈)alkyl" refers to a heterocyclic(C₁ -C₁₈)alkyl group as previouslydefined substituted in the heterocyclic group with one or moresubstitutents defined above for heterocyclic and/or substituted in thealkyl group with one or more substitutents defined above for (C₁-C₁₈)alkyl. Examples of such groups are (substitutedheterocyclic)-lower-alkyl such as (substituted heterocyclic)methyl,(substituted heterocyclic)ethyl, (substituted heterocyclic)propyl,(substituted heterocyclic)iso-propyl, (substituted heterocyclic)butyl,(substituted heterocyclic)pentyl and (substituted heterocyclic)hexyl,heterocyclic(substituted loweralkyl) such as pyrrolyl(substitutedloweralkyl), indolyl(substituted loweralkyl), quinolyl(substitutedloweralkyl), tetrahydroquinolyl(substituted loweralkyl),pyridyl-(substituted loweralkyl), morpholinyl(substituted loweralkyl),piperidinyl(substituted loweralkyl), thiomorpholinyl(substitutedloweralkyl), thienyl(substituted loweralkyl), furanyl(substitutedloweralkyl), benzfuranyl(substituted loweralkyl),pyrrolidinyl-(substituted loweralkyl) and iso-quinolyl(substitutedloweralkyl), and (substituted heterocyclic)(substituted loweralkyl),wherein in each case substituted heterocyclic is as exemplified abovewith respect to "optionally substituted heterocyclic" and (substitutedloweralkyl) is as exemplified above with respect to "optionallysubstituted (C₁ -C₁₈)alkyl".

As used herein, the term "optionally substituted heterocyclic(C₁-C₁₈)alkenyl" refers to a heterocyclic(C₁ -C₁₈)alkenyl group aspreviously defined substituted in the heterocyclic group with one ormore substitutents defined above for heterocyclic and/or substituted inthe alkenyl group with one or more substitutents defined above for (C₁-C₁₈)alkenyl.

As used herein, the term "optionally substituted heterocyclic(C₁-C₁₈)alkynyl" refers to a heterocyclic(C₁ -C₁₈)alkynyl group aspreviously defined substituted in the heterocyclic group with one ormore substitutents defined above for heterocyclic and/or substituted inthe alkynyl group with one or more substitutents defined above for (C₁-C₁₈)alkynyl.

As used herein, the term "optionally substituted alkylidene" refers toan alkylidene radical as previously defined, in which one or morehydrogen atoms is replaced by substituent(s) independently selected fromthe substituents defined above in connection with "optionallysubstituted (C₁ -C₁₈)allyl".

As used herein, the term "naturally occurring or synthetic amino acid"refers to a compound of the formula HN(R₄₀₁)(CH(R₄₀₀))_(p) COOH, whereinR₄₀₀ and R₄₀₁ independently have the meaning of R₂₀ as previouslydefined, and p is 1, 2 or 3, and wherein R₄₀₀ and R₄₀₁, together withthe carbon and nitrogen to which they are bound may together form asaturated or unsaturated cyclic, bicyclic or fused ring system. Examplesof naturally occurring or synthetic amino acids include alanine,cyclohexylalanine, anthranilic acid, arginine, asparagine, asparticacid, cysteine, β-phenylcysteine, cystine, glutamic acid, glutamine,glycine, cyclohexylglycine, tetrahydrofuranylglycine, histidine,homoserine, hydroxyproline, isoleucine, leucine, lysine, 4-azalysine,δ-hydroxylysine, methionine, norleucine, norvaline, ornithine,phenylalanine, 4-aminophenylalanine, 4-carboxyphenylalanine,4-chlorophenylalanine, phenylglycine, 8-phenylserine, proline, serine,threonine, trans-3-hydroxyproline, trans4-hydroxyproline, tryptophan,tyrosine, valine, indoline-2-carboxylic acid,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid,aminomalonic acid monoamide, α-aminobutyric acid, α,γ-diaminobutyricacid and α,β-diaminopropionic acid. Other amino acids, and peptidesderived therefrom, are disclosed in J. S. Davies, ed., Amino Acids andPeptides, Chapman and Hall, London, 1985, the disclosure of which isincorporated herein by reference.

As used herein, the term "residue of a naturally occurring or syntheticamino acid" refers to a group of the formula --N(R₄₀₁)(CH(R₄₀₀))_(p)C(O)--, wherein R₄₀₀, R₄₀₁, and p are as defined above with regard to"naturally occurring or synthetic amino acid".

As used herein, the term "azaamino acid" refers to an amino acid inwhich a --CH(R₄₀₀)-- group has been replaced by a group ---(R₄₀₁)--,wherein R₄₀₁ has the meaning of R₂₀ as previously defined.

Suitable pharmaceutically acceptable salts of the compound of formula(I) are, where the compound of formula (I) contains a basic nitrogenatom, acid addition salts of pharmaceutically acceptable inorganic acidssuch as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric,sulfamic, hydrobromic or hydriodic, or with pharmaceutically acceptableorganic acids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, methylmaleic, fumaric, malic, citric, lactic, mucic,gluconic, glucoheptonic, glucaric, glucuronic, lactobionic, benzoic,naphthoic, succinic, oxalic, phenylacetic, methanesulphonic,ethanesulfonic, 2-hydroxyethanesulfonic, ethane-1,2-disulfonic,laurylsulfonic, toluenesulphonic, benzenesulphonic,naphthalene-2-sulfonic, salicylic, 4-aminosalicylic, sulphanilic,aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric,pantothenic, tannic, ascorbic, valeric, glycolic, cinnamic, mandelic,2-phenoxybenzoic, 2-acetoxybenzoic, embonic, nicotinic, isonicotinic,N-cyclohexylsulfamic or other acidic organic compounds, such as 2- or3-phosphoglycerate and glucose-6-phosphate. Where the compound offormula (I) contains an acid group, suitable pharmaceutically acceptablesalts of the compound of formula (I) are addition salts ofpharmaceutically acceptable bases such as lithium, sodium, potassium,ammonium, magnesium, calcium and zinc salts, or salts formed withorganic amines such as methylamine, dimethylamine, trimethylamine,ethylamine, diethylamine, triethylamine, N-methyl-N-ethylamine, mono-,bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine,tris(hydroxymethyl)methylamine, N,N-dimethyl-N-(2-hydroxyethyl)-amine,tri-(2-hydroxyethyl)-amine, N-methyl-D-glucamine, or tributylamine.Compounds of formula I having acid and basic groups can also forminternal salts. Other suitable salts are described, for example, in S.M. Berge, et al., "Pharmaceutical Salts" J. Pharm. Sci., 66 1-19 (1977)which is incorporated herein by reference.

The expression "prodrug" as used herein refers to a pharmaceuticallyacceptable derivative of a compound of formula (I) which is transformedinto a compound of formula (I) after administration of the prodrug to aliving animal or human, and which has enhanced stability, deliverycharacteristics and/or therapeutic value compared to the compound offormula (I) from which it derives.

The expression "protecting group" as used herein refers to a group whichmay be used temporarily to modify a functional group, for example toprevent that functional group from being affected by, or fromundesirably affecting the outcome of, a desired reaction involvinganother functional group in the molecule and/or to prevent prematuremetabolism of the compound of formula (I) after administration to apatient before the compound can reach the desired site of action.Suitable protecting groups are described, for example in Greene, T. W.,Protective Groups in Organic Synthesis (John Wiley & Sons, New York,1981) and McOmie, J. F. W., Protective Groups in Organic Chemistry(Plenum Press, London, 1973).

Examples of suitable protecting groups for hydroxyl or mercaptosubstituents include substituted methyl ethers, for example,methoxymethyl, benzyloxymethyl, t-butyloxymethyl, 2-methoxyethoxymethyl,1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl, benzyl, allyl,triphenylmethyl and the like, other etherifying groups such as2-tetrahydrofuryl, 2-tetrahydropyranyl and vinyl, or by acyl andcarbonate groups such as formyl, 2,2-dichloroacetyl,2,2,2-trichloroacetyl, t-butyloxycarbonyl, benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, and 4-methoxybenzyloxycarbonyl, or by silylgroups such as trimethylsilyl, t-butyldimethylsilyl, tribenzylsilyl,triphenylsilyl and the like.

Suitable protecting groups for amino substituents include acyl groupssuch as formyl, acetyl, 3-phenylpropionyl, chloroacetyl,trifluoroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl,4-methoxybenzoyl, t-butyloxycarbonyl, benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl,(2-pyridyl)methoxycarbonyl, quinoline-2-carbonyl,2-trimethylsilylethoxycarbonyl, or trimethylsilyl, or an aminoacylresidue.

Suitable protecting groups for carboxyl substituents include esters, forexample methyl, ethyl, tert-butyl, benzyl, 4-nitrobenzyl,4-methoxybenzyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl,methylthiomethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl,2-trimethylsilylethyl, 2-triphenylsilylethyl, t-butyldimethylsilyl ortrimethylsilyl esters.

Suitable protecting groups for carbonyl substituents include acetalssuch as dimethyl, diethyl, dibutyl and dibenzyl, thioacetals such asS,S-dimethyl and S,S-diethyl, cyclic acetals and thioacetlas such as1,3-dioxanes, 1,3-dioxolanes, 1,3-oxathiolanes, 1,3-dithianes and1,3-dithiolanes, and oximes and hydrazones such as O-benzyl oximes,O-phenylthiomethyl oximes and N,N-dimethyl hydrazones.

The expression "solubilising group Px" as used herein refers to a groupwhich may be used to derivatise a functional group so as to enhance thesolubility of the compound of formula (I) in water or aqueous media.Examples of solubilising groups for inclusion in the compound of formula(I) are groups of the formula Px* or salts thereof, where Px* isselected from: ##STR25## wherein R and R' are independently hydrogen orC₁ -C₄ alkyl. Also included within the meaning of Px are groups of thefollowing formulae, wherein Px* and D are as previously defined, and Ris H or C₁ -C₄ alkyl: ##STR26##

Where the compound of formula (I) includes two functional groups capableof being derivatised by a solubilising group, the two funtional groupsbeing in sufficiently close proximity to one another, it will beappreciated that certain of the solubilising groups exemplified aboveare capable of forming cyclic structures, for example including thefollowing structural units: ##STR27## wherein X₁ and X₂ areindependently selected from O, S and NR₆ wherein R₆ is as previouslydefined. Solubilising groups in a cyclic structure, such as thoseexemplifed above, also fall within the meaning of "solubilising group"as used herein.

Where the solubilising group is acidic, a salt thereof is typically asalt of an alkali metal or ammonia, such as Na⁺, K⁺ or NH₄ ⁺. Where thesolubilising group is basic, a salt thereof is typically a salt of astrong inorganic acid such as hydrochloric acid, sulfuric acid,phosphoric acid or nitric acid. Typically, the solubilising group is asodium or potassium salt of a phosphate or phosphite residue.

Solubilising or protecting groups which are included in the compound offormula (I) must be amenable to hydrolytic or metabolic cleavage invivo.

In one form of the present invention, in the compound of the generalformula (I), B is typically selected from the group consisting of##STR28## where Z, Z*, M, M₁, M₂, D*, R₁₄, R_(14*), R_(14**), R₁₅, R₁₈,R_(18*), R₁₉ and R_(9*) are as previously defined, and V is YR₂, Y* orC(R₃₀)═Y**, wherein R₂, R₃₀ and Y** are as previously defined, andwherein Y is selected from the group consisting of ##STR29## and Y* isselected from the group consisting of ##STR30## wherein R₃₃, R₃₄, R₅₀,R₅, and R_(2*) are as previously defined.

More typically, the compound of the general formula (I) in this form ofthe invention has the structure represented by formula (IA): ##STR31##where R_(1*), R₁₀, R₁₂, R_(12*), R₁₃ and R_(13*) are as previouslydefined, B* is selected from the group consisting of ##STR32## where Z,Z*, M, M₁, M₂, D*, R₁₄, R_(14*), R_(14**), R₁₈ and R₁₉ are as previouslydefined, and Y₁ is selected from the group consisting of ##STR33##wherein R₅₀, R₅₁, and R_(2*) are as previously defined.

Even more typically, the compound of the general formula (I) in thisform of the invention has the structure represented by formula (IB):##STR34## wherein x and y are independently 0 or 1, B is selected fromthe group consisting of ##STR35## wherein R_(14*), R_(14**), R₁₅, R₁₈and R₁₉ are as previously defined and each R₅₆₀ is independentlyhydrogen or (C₁ -C₄)alkyl,

R₅₀₂ and R₅₀₆ are independently a group R₆₀₀, wherein R₆₀₀ is selectedfrom the group consisting of hydrogen, C(O)OR₆₂₁, C(O)SR₆₂₁, C(O)NR₆₂₁R₆₂₂, (C₁ -C₆)alkyl, (C₂ -C₆)alkenyl, (C₅ -C₁₀)cycloalkyl, (C₅-C₁₀)cycloalkyl(C₁ -C₆)alkyl, (C₅ -C₁₀)cycloalkyl(C₂ -C₆)alkenyl, (C₆-C₁₀)aryl, (C₆ -C₁₀)aryl(C₁ -C₆)allyl, (C₆ -C₁₀)aryl(C₂ -C₆)alkenyl, (C₁-C₆)acyl, heterocyclic, heterocyclic(C₁ -C₆)alkyl and heterocyclic(C₂-C₆)alkenyl, each of which may be substituted by up to threesubstituents selected from the substituents defined above for"optionally substituted (C₁ -C₁₈)alkyl" and R₆₂₁ and R₆₂₂ have themeaning of R₂₁ and R₂₂ respectively, as previously defined, or R₆₂₁ andR₆₂₂ together form a saturated or unsaturated cyclic, bicyclic or fusedring system as defined below,

R₅₀₁ is selected from the group consisting of R₆₀₀ as previouslydefined, S(O)OR₆₃₂, S(O)₂ R₆₃₂, S(O)NR₆₃₂ R₆₃₃, S(O)₂ R₆₃₂ R₆₃₃, NH₂,NHR₆₃₁ and NR₆₃₁ R₆₃₂, wherein R₆₃₁ has the meaning of R₆ as previouslydefined and R₆₃₂ and R₆₃₃ independently have the meaning of R₂₀ aspreviously defined, or R₅₀, and R₅₀₆ together form part of a saturatedor unsaturated cyclic, bicyclic or fused ring system, or R₆₃₁ and R₆₃₂,or R₆₃₂ and R₆₃₃ together form a saturated or unsaturated cyclic,bicyclic or fused ring system as defined below,

R₅₁₂ and R₅₄₂ independently have the meaning of R₆₀₀ as previouslydefined, R₅₂₂ and R₅₃₂ are independently selected from the groupconsisting of R₆₀₀ as previously defined, F, Cl, Br and I, R₅₁₃ and R₅₄₃are independently selected from the group consisting of R₆₀₀ aspreviously defined and R₂₀₀ as previously defined,

R₅₂₃ and R₅₃₃ are independently selected from the group consisting ofR₆₀₀ as previously defined, F, Cl, Br, I, and R₂₀₀ as previouslydefined,

R₅₅₀ has the meaning of R₆ as previously defined and R₅₅₁ is selectedfrom the group consisting of R₆₅₀, hydrogen, S(O)OR₆₃₂, S(O)₂ R₆₃₂,S(O)NR₆₃₂ R₆₃₃ and S(O)₂ R₆₃₂ R₆₃₃, wherein R₆₅₀ has the meaning of R₆as previously defined and R₆₃₂ and R₆₃₃ are as previously defined, orR₆₃₂ and R₆₃₃ together form a saturated or unsaturated cyclic, bicyclicor fused ring system as defined below, or R₅₅₀ and one of R₅₅, and R₅₀₂together form a diazaheterocycle wherein R₅₅₀, R₅₅₁ or R₅₀₂ and the twonitrogen atoms to which they are bonded are part of a stable 5 to10-membered ring which may comprise up to two further heteroatomsselected from O, S and N and to which may be fused one or morecycloalkyl, cycloalkenyl, aryl or heterocyclic residues, whichdiazaheterocycle may be substituted by one or more of the substituentsdefined above for "optionally substituted (C₁ -C₁₈)alkyl", and whereintwo substituents may together form part of a ring,

or one pair selected from R₅₁₂ and R₅₁₃, R₅₂₂ and R₅₂₃ (when present),R₅₃₂ and R₅₃₃ (when present), and R₅₄₂ and R₅₄₃, together are ═O;

wherein, when B is other than ##STR36## then at least one of conditions(i) to (xi) below applies: (i) at least one of R₅₁₂ and R₅₄₂ is a groupR wherein R₆₅₅ is selected from the group consisting of (C₁ -C₆)alkyl(C₆-C₁₀)aryl, (C₂ -C₆)alkenyl-(C₆ -C₁₀)aryl, (C₅ -C₁₀)cycloalkyl(C₂-C₆)alkenyl, (C₅ -C₁₀)cycloalkyl-(C₆ -C₁₀)aryl, acyl(C₆ -C₁₀)aryl,heterocyclic(C₁ -C₆)alkyl, heterocyclic(C₂ -C₆)alkenyl, heterocyclic(C₆-C₁₀)aryl, C(D*)OR_(21*), C(D*)SR₂₁ * and C(D*)NR_(21*) R_(22*), whereinD*, R_(21*), and R_(22*) are as previously defined,

(ii) at least one of R₅₂₂ and R₅₃₂, when present, is selected from thegroup consisting of R₆₅₅ as previously defined, F, Cl, Br and I,

(iii) at least one of R₅₁₃ and R₅₄₃, when present, is selected from thegroup consisting of R₆₅₅ as previously defined, and R₂₀₀ as previouslydefined,

(iv) at least one of R₅₂₃ and R₅₃₃, when present, is selected from thegroup consisting of R₆₅₅ as previously defined, F,Cl Br, I and R₂₀₀ aspreviously defined,

(v) R₅₅₀ is a group R₆₅₆, wherein R₆₅₆ is selected from the groupconsisting of (C₁ -C₆)alkyl(C₆ -C₁₀)aryl, (C₂ -C₆)alkenyl(C₆ -C₁₀)aryl,(C₅ -C₁₀)cycloalkyl(C₂ -C₆)alkenyl, (C₅ -C₁₀)cycloalkyl(C₆ -C₁₀)aryl,acyl(C₆ -C₁₀)aryl, heterocyclic(C₁ -C₆)alkyl, heterocyclic(C₂-C₆)alkenyl, heterocyclic(C₆ -C₁₀)aryl,

(vi) R₅₅₁ is selected from the group consisting of R₆₅₆ as previouslydefined, S(O)OR₆₃₂, S(O)₂ R₆₃₂, S(O)NR₆₃₂ R₆₃₃ and S(O)₂ R₆₃₂ R₆₃₃,wherein R₆₃₂ and R₆₃₃ are as previously defined,

(vii) R₅₀₂ is selected from the group consisting of R₆₅₆ as previouslydefined, C(D*)SR_(21*) and C(D*)NR_(21*) R_(22*), wherein D*, R_(21*)and R_(22*) are as previously defined,

(viii) R₅₀₂ and R₅₅₁ are both hydrogen or are both (C₁ -C₆)acyl,

(ix) R_(14*) is selected from the group consisting of C(D*)OR₄₀,C(D*)SR₄₀ and C(D*)NR₄₀ R₄₁, wherein R₄₀ and R₄₁, are as previouslydefined,

(x) R₅₀₁ is selected from the group consisting of R₆₅₆ as previouslydefined, S(O)OR₆₃₂, S(O)₂ R₆₃₂, S(O)NR₆₃₂ R₆₃₃, S(O)₂ R₆₃₂ R₆₃₃, NH₂,NHR₆₃₁ and NR₆₃₁ R₆₃₂, wherein R₆₃₂ and R₆₃₃ are as previously defined,

(xi) R₅₀₁ and R₅₀₆ are both (C₁ -C₆)acyl,

and wherein when B is ##STR37## then at least one of the followingconditions also applies: (xii) x+y>0,

(xiii) x+y=0 and at least one of R₅₃₂ and R₅₃₃ is other than hydrogen,

(xiv) R₅₀ and R₅₁ together form a diazaheterocycle as previouslydefined,

(xv) at least one of R₅₀₁, R₅₀₂, R₅₀₆ and R₅₅₁ is optionally substitutedheterocyclic(C₁ -C₁₈)alkyl, and

(xvi) at least one of R₅₁₂, R₅₄₂, R₅₂₂, R₅₃₂, R₅₁₃, R₅₄₃, R₅₂₃ and R₅₃₃is selected from the group consisting of C(O)O₆₂₁, C(O)SR₆₂₁ andC(O)NR₆₂₁ R₆₂₂, wherein R₆₂₁ and R₆₂₂ are as previously defined.

Examples of typical unsubstituted diazaheterocycles are: ##STR38##

Other forms of the first embodiment of the invention have the structuresrepresented by formulae (IC) to (IAW) below, in which each AA isindependently a residue of a naturally occurring or synthetic amino acidas herein defined ; R_(1*), R₁, X and X* are as previously defined; Rato Rj independently are --(CH₂)_(a-6) OPy, wherein a can be 0, 1, 2, 3,4 or 5, halogen or R₆, more typically --(CH₂)₀₋₃ OPy, fluoro, chloro orR_(6*) wherein Py is a solubilising group Px as defined herein, R₆ is aspreviously defined and R_(6*) is is selected from the group consistingof

hydrogen,

R_(20*), wherein R_(20*) is selected from the group consisting of

optionally substituted (C₁ -C₆)alkyl,

optionally substituted (C₂ -C₆)alkenyl,

optionally substituted (C₂ -C₆)alkynyl,

optionally substituted (C₃ -C₈)cycloalkyl,

optionally substituted (C₃ -C₈)cycloalkyl(C₁ -C₆)alkyl,

optionally substituted (C₃ -C₈)cycloalkyl(C₂ -C₆)alkenyl,

optionally substituted (C₃ -C₈)cycloalkyl(C₂ -C₆)alkynyl,

optionally substituted (C₆ -C₁₀)aryl,

optionally substituted (C₆ -C₁₀)aryl(C₁ -C₆)alkyl,

optionally substituted (C₆ -C₁₀)aryl(C₂ -C₆)alkenyl,

optionally substituted (C₁ -C₆)acyl,

optionally substituted heterocyclic, and

optionally substituted heterocyclic(C₁ -C₆)alkyl,

C(O)OR₂₁,

C(O)SR₂₁, and

C(O)NR₂₁ R₂₂, wherein R₂₁ and R₂₂ independently are selected fromhydrogen and R_(20*) as previously defined, or R₂₁ and R₂₂ together forma saturated or unsaturated cyclic, bicyclic or fused ring system aspreviously defined: ##STR39## wherein D'is O or S, and each G isindependently hydrogen or R₂₀₀ as previously defined and wherein R'_(d)and R'_(f) are R_(d) and R_(f) or, taken together, may be trimethyleneor tetramethylene optimally substituted with --C(O)OR; or --C(O)NR_(i)R_(j) ; ##STR40## wherein G is selected from R_(1*) and X*R_(1*) ;##STR41## wherein R_(a) ' is OPy or R₆ as previously defined, M₁ is R₆as previously defined, (CH₂)₁₋₂ OPy or (CH₂)₁₋₂ NHPy, and G* is OR₂ orNR_(i) R₂ ; ##STR42## wherein G is hydrogen, R_(a), R_(1*) X* or R_(1*)X*C(R_(a))(R_(b))C(O), and wherein R_(a), R_(1*), and the atoms to whichthey are bound may optionally form a saturated or unsaturated cyclic,bicyclic or fused ring system; ##STR43## wherein R_(a), R_(1*), and theatoms to which they are bound may optionally form a saturated orunsaturated cyclic, bicyclic or fused ring system; ##STR44## wherein W₂is R₁ X or R₆ as previously defined, and R' is Py or R₆ as previouslydefined, or R' and Py, taken together with the oxygen atoms to whichthey are attached form a group selected from ##STR45## wherein each L isindependently as previously defined and each Pz is independentlyhydrogen or Py, provided that at least one Pz is Py or, when each Pz isPy, the groups Py, together with the oxygen atoms to which the are bounddefine a cyclic group selected from ##STR46## wherein Q is O or NR_(f)and G is R_(1*) or X*R_(1*) ; ##STR47## wherein each ##STR48## isindependently a 5- or 6- membered saturated or unsaturated heterocyclecontaining a nitrogen atom and optionally additionally one or twoheteroatoms selected from nitrogen, oxygen and sulfur, and wherein R_(a)' and R_(b) ' independently have the meaning of --(CH₂)₀₋₆ OPy or R₆, ortaken together are ═O; ##STR49## wherein W₁ is selected from R₁ X andR_(1*) X*, and Q is selected from O and NR_(h) ; ##STR50## wherein W₁ isselected from R₁ X and R_(1*) X*, each Pz is independently hydrogen orPy, provided that at least one Pz is Py, and Q is selected from O andNR_(h) ; ##STR51## wherein each Pz is independently hydrogen or Py,provided that at least one Pz is Py; ##STR52## wherein ##STR53## is a 5-or 6- membered saturated or unsaturated heterocycle containing anitrogen atom and optionally additionally one or two heteroatomsselected from nitrogen, oxygen and sulfur; ##STR54## wherein R_(a) ' andR_(j) ' are independently selected from R₁ and R_(1*), as previouslydefined; ##STR55## wherein G is selected from ##STR56## and a saturatedor unsaturated cyclic, bicyclic or fused ring system, Q is O or NH, andG* is X or X* as previously defined; ##STR57## wherein ##STR58## is a5-12 membered saturated or unsaturated cyclic, bicyclic or fused ringsystem containing a nitrogen atom and optionally additionally from 1 to4 heteroatoms selected from nitrogen, oxygen and sulfur; ##STR59##wherein G is selected from hydrogen and R_(1*) X*, Q is O, S or NH, Q*is O or NH, and G₁ is selected from R₁ and R_(1*) X*; ##STR60## whereinR₂ 00 is as previously defined; ##STR61## wherein ##STR62## is anoptionally substituted 5-12 membered saturated or unsaturated cyclic,bicyclic or fused ring system containing a nitrogen atom and optionallyadditionally from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur; ##STR63## wherein b is 0, 1 or 2, provided that at least one bis greater than 0, and each Pz is independently hydrogen or Py, providedthat at least one Pz is Py; ##STR64## wherein each G* is independentlyselected from O, S and NR₆ and G is selected from OR₆, NHR₆ and R₂₀ ;##STR65## wherein G is --C(O)-- or --CH₂ --, G* is R₁ or R_(1*), G** is--O-- or --NR_(h) --, Q is --O-- or --NR_(i) and Pz is selected from thegroup consisting of ##STR66## wherein R and R' are independentlyhydrogen or C₁ -C₄ alkyl, D is 0 or S and Px* is as previously defined ;##STR67## wherein G is R₁ or R_(1*), G* is --O-- or --NR_(f) -- and Pzis selected from the group consisting of ##STR68## wherein R and R' areindependently hydrogen or C₁ -C₄ alkyl, D is O or S and Px* is aspreviously defined; ##STR69## wherein G is R₁ or R_(1*), and each Q isindependently H, --OPz or --NR_(d) Pz, wherein each P_(z) isindependently hydrogen or Py, provided that at least one Pz is Py;##STR70## wherein ##STR71## is a saturated or unsaturated cyclic,bicyclic or fused nitrogen containing ring system and G is a bond or is--O-- or --NR_(f) ; ##STR72## wherein G is absent or X*R_(1*) and##STR73## is a 3 to 10-membered saturated or unsaturated heterocyclecontaining a nitrogen atom and optionally additionally one to threeheteroatoms selected from nitrogen, oxygen and sulfur; ##STR74## whereinQ is selected from --O--, --S-- and --NR_(f) --; ##STR75## wherein G isO, S, S(O) or S(O)₂, and R_(a) ' and R_(b) ' have the meaning of R_(a)and R_(b) or R_(a'). and R_(b') together are trimethylene ortetramethylene; ##STR76## wherein each Ar is independently (C₆-C₁₄)aryl, R'_(c) and R'_(d) are R_(c) and R_(d) or, taken together, are--C(O)-- or --CH(OH)--, and wherein Pz and Pz' are independentlyhydrogen or Py with the proviso that at least one of Pz and Pz' is Py,or Pz and Pz' together with the oxygen atoms to which they are attachedform a group selected from ##STR77## wherein G is a bond or X aspreviously defined, R_(g) ' and R_(h) ' are R_(g) and R_(h) or togetherform a saturated or unsaturated cylic, bicylic or fused ring system, andPz and Pz' are independently hydrogen or Py with the proviso that atleast one of Pz and Pz' is Py, or Pz and Pz' together with the oxygenatoms to which they are attached form a group selected from ##STR78##wherein G is a bond, O. S or NR_(j), R_(g) ' and R_(h) ' are R_(g) andR_(h), or taken together may be --C(O)--, and Pz and Pz' areindependently hydrogen or Py with the proviso that at least one of Pzand Pz' is Py, or Pz and Pz' together with the oxygen atoms to whichthey are attached form a group selected from ##STR79## wherein G is OPy,NHR_(e), NPyR_(e) or R_(e) ; ##STR80## wherein G and G* areindependently a bond, O, S or NH, and R'_(d) and R_(h) ' are Rd and Rhor taken together are --CR'₂ -- or --CR₂ '--CR₂ '-- wherein each R'independently has the meaning of R₆ as previously defined, Q and Q* areindependently N or CR₆, or when Q* is CR₆ then R_(g) and R₆ together maybe a double bond; ##STR81## wherein G is --C(O)-- or --C(R₆)(CH₂)₀₋₄ OG*wherein G* is R₆ or Py; ##STR82## wherein G is selected from hydrogenand X*R_(1*) and wherein ##STR83## represents a 4-10 membered saturatedor unsaturated cyclic, bicylic or fused ring system as defined herein;##STR84## wherein Q is selected from O, S and NR_(g), G and G* areindependently selected from R₁, R_(1*), --C(R₅)═NR₃ and --C(R₅)═NOR₃,wherein R₃ and R₅ are as previously defined, R'_(e) and R'_(f) are R_(e)and R_(f), and G** is R₂₀ as previously defined; ##STR85## wherein eachR_(z) is independently selected from R₁ and PyOG* wherein G* isoptionally substituted alkylelne, provided that at least one R_(z) isPYOG*, and G is --NR_(d) -- or CR_(d) R_(e) --; ##STR86## wherein##STR87## represents an optionally substituted saturated or unsaturatedring system optionally containing up to three heteroatoms selected fromN, O and S, G is selected from R₁, XR₁ or X*R_(1*) and R_(a) and R_(b)taken together may optionally be --C(O)--; ##STR88## wherein B* is agroup B, as previously defined, derivatised with a solubilising groupPy; ##STR89## wherein ##STR90## represents an optionally substitutedcyclic, bicyclic or fused ring system containing a nitrogen atom andoptionally additionally from 1 to 3 heteroatoms selected from N, O andS; ##STR91## wherein Q₁ and Q₂ are independently selected from 0 and S,and R'_(f) and R'_(g) are respectively R_(f) and R_(g) or are selectedfrom OR', SR' and NR_(h) R' wherein R' is H, R_(i) or Py; ##STR92##wherein each G is independently selected from O and NR_(i), and R' is(CH₂)₁₋₂ OPy or R₆ ##STR93## wherein G and G* are independently selectedfrom ##STR94## and L, wherein L is as previously defied and Q is H orPy, provided that at least one of G and G* is other than L and providedthat at least one Q is Py, or wherein two groups OQ taken together are acyclic group slected from ##STR95## wherein R_(x) and R_(y) areindependently R₆ or (CH₂)₁₋₂ OPy; ##STR96## wherein G and G* areindependently selected from R₁, R_(1*), --C(R₅)═NR₃ and --C(R₅)N═OR₃,wherein R₃ and R₅ are as previously defined.

Still other compounds of the first embodiment are those compoundsexemplified in International Patent Application no. WO 93/18006, namely:

(i) t-butyl 3-isopropyl-3- (2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)-amino4-phenylbutyl!carbazate,

(ii) t-butyl 3-isopropyl-3- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-valyl)-amino4-phenylbutyl!carbazate,

(iii) t-butyl 3-isopropyl-3- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!carbazate,

(iv) t-butyl 3-(1-methyl-3-phenylpropen-3-yl)-3- (2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl!carbazate,

(v) t-butyl 3-(1-methyl-3-phenylpropyl)-3- (2R or S,3S)-2-hydroxy-3-(N-quialdoyl-L-asparaginyl)amino-4-phenylbutyl!carbazate,

(vi) cis-1,6-3-t-butoxycarbonyl-4- (2R or S,3S)-2-hydroxy-3-amino4-phenylbutyl!-3 ,4-diazabicyclo 4.4.0!decane,

(vii) cis-1,6-3-t-butoxycarbonyl4- (2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino4-phenylbutyl!-diazabicyclo4.4.0!decane,

(viii) cis-1,6-3-t-butoxycarbonyl4- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-valyl)amino4-phenylbutyl!-3,4-diazabicyclo4.4.0!decane,

(ix) cis-1,6-3-t-butoxycarbonyl4- (2R or S, 3S)-2-hydroxy-3-N-(2-pyridyl)-methoxycarbonyl)-L-valyl)amino4-phenylbutyl!-3,4-diaza-bicyclo4.4.0!-decane,

(x) cis-1,6-3-t-butoxycarbonyl4- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!-3,4-diazabicyclo4.4.0!decane,

(xi) cis-1,6-3-t-butoxycarbonyl4- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-glutaminyl)amino4-phenylbutyl!-3,4-diazabicyclo4.4.0!decane,

(xii) cis-1,6-3-t-butoxycarbonyl4- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-threonyl)amino4-phenylbutyl!-3,4-diazabicyclo4.4.0!decane,

(xiii) 2-t-butoxycarbonyl-3- (2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)-amino4-phenylbutyl!-2,3-diazabicyclo2.2.1 !hept-5-ene,

(xiv) 2-t-butoxycarbonyl-3- (2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)-amino-4-phenylbutyl!-2,3-diaza-bicyclo2.2.1!heptane,

(xv) 2-t-butoxycarbonyl-3- (2R or S,3S)-2-hydroxy-3-(N-(2-pyridyl)methoxy-L-valyl)amino4-phenylbutyl!-2,3-diaza-bicyclo2.2.1!heptane,

(xvi) 2- N-(1S)(2-methyl-1-methoxycarbonylpropyl)carbamoyl!-3- (2R or S,3S)-2-hydroxy-3-N-(2-pyridyl)methoxy-L-valyl!amino-4-phenylbutyl!-2,3-diazabicyclo2.2.1!heptane,

(xvii) 2-t-butoxycarbonyl-3- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!-2,3-diazabicyclo2.2.1!heptane,

(xviii) 1- 2-(2-pyridyl)methoxycarbonylamino-!benzoyl-2- (2R or S,3S)-2-hydroxy3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!-2-isopropyl-hydrazine,

(xix) 2-t-butoxycarbonyl-3- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!-1,2,3,4-tetrahydrophthalazine,

(xx) 1-trimethylacetyl-2- (2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)-amino4-phyenylbutyl!-2-isopropylhydrazine,

(xxi) 1-trimethylacetyl-2- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!-2-isopropylhydrazine,

(xxii) 1-(t-butylamino)carbonyl-2- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!-2-isopropylhydrazine,

(xxiii) t-butyl 3-isopropyl-3- (2R or S,3S)-2-hydroxy-3-(N-picolinoyl-L-asparaginyl)amino4-phenylbutyl!carbazate,

(xxiv) t-butyl 3-isopropyl-3- (2R or S,3S)-2-hydroxy-3-(N-(2-pyridyl)-methoxycarbonylanthraniloyl)amino4-phenylbutyl!carbazate.

(xxv) t-butyl 3-benzyl-3- (2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)-amino4-phenylbutyl!carbazate,

(xxvi) t-butyl 3-benzyl-3- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)-amino4-phenylbutyl!carbazate,

(xxvii) t-butyl 3-cyclohexyl-3- (2R or S,3S)-2-hydroxy-3-(phenyl-methoxycarbonyl)amino4-phenylbutyl!carbazate,

(xxviii) t-butyl 3-cyclohexyl-3- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!carbazate,

(xxix) t-butyl 3-isopropyl-3- (2R or S,3S)-2-hydroxy-3-(N-(1-carbamoyl-methyl)-acryloyl)amino4-phenylbutyl!carbazate,

(xxx) t-butyl 3-isopropyl-3- (2R or S,3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio2-carbamoyl-methylpropionyl)amino4-phenylbutyl!carbazate,

(xxxi) t-butyl 3-isopropyl-3- (2R or S,3S)-2-hydroxy-3-(N-(1-benzoyl-L-asparaginyl)amino4-phenylbutyl!carbazate,

(xxxii) 1-t-butyloxycarbonyl-2- (2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino4-phenylbutyl!hexahydropyridazine,

(xxxiii) 1-t-butyloxycarbonyl-2- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!hexahydropyridazine,and

(xxxiv) cis-1,6-3-t-butoxycarbonyl4- (2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-3-cyano-L-alanyl)amino4-phenylbutyl!-3,4-diaza-bicyclo 4,4,O!decane,

wherein the 2-hydroxy group has been derivatised with a solubilisinggroup Px as herein defined. Typically, in this form of the firstembodiment, compounds (i) to (xxxiv) referred to above are derivatisedwith a solubilising group selected from ##STR97##

The compounds of formulae (I) to (IAW) can exist in optically isomericforms and the present invention includes within its scope all theseforms in all proportions including all diastereoisomers and mixturesthereof and all enantiomers, mixtures of enantiomers and racemicmixtures. Where a double bond occurs in the compound of the invention,the double bond may be present in the cis- (Z) or trans- (E)configuration. It will be understood that only compounds of formula (I)with combinations of substituents or functional groups which give riseto stable compounds, are within the scope of the present invention.

The compounds of general formula (I) may be prepared by methods knowngenerally in the art. Suitable methods for the synthesis of compounds offormula (I) and intermediates thereof are described, for example, inHouben-Weyl, Methoden der Organischen Chemie; J. March, Advanced OrganicChemistry, 3rd Edition (John Wiley & Sons, New York, 1985); D. C. Liottaand M. Volmer, eds, Organic Syntheses Reaction Guide (John Wiley & Sons,Inc., New York, 1991); R. C. Larock, Comprehensive OrganicTransformations (VCH, New York, 1989), H. O. House, Modern SyntheticReactions 2nd Edition (W. A. Benjamin, Inc., Menlo Park, 1972); N. S.Simpkins, ed. 100 Modern Reagents (The Royal Society of Chemistry,London, 1989); A. H. Haines Methods for the Oxidation of OrganicCompounds (Academic Press, London, 1988) and B. J. WakefieldOrganolithium Methods (Academic Press, London, 1988).

For example, a compound of formula (I) may be prepared from synthons W*,{(A)_(n) B-(A*)_(m) }* and V*, wherein each synthon identified thus * isa synthetic precursor of the corresponding portion of the moleculeW--(A)_(n) --B--(A*)_(m) --V. Thus, a compound of formula (I) may beprepared, for example, in any of the following ways:

(a) by reaction of W--(A)_(n) --B--(A)_(m) --G with H--V;

(b) by reaction of W--(A)_(n) --B--(A)_(m) --H with G--V;

(c) by reaction of W--H with G--(A)_(n) --B--(A)_(m) --V; and

(d) by reaction of W--G with H--(A)_(n) --B--(A)_(m) --V;

wherein G is a leaving group such as halogen, typically chlorine,bromine or iodine; a sulfonate such as methanesulfonate,trifluoromethanesulfonate, benzenesulfonate or toluenesulfonate; analkoxy, thioalkoxy, aryloxy or thioaryloxy group such as ethoxy,methoxy, thiomethoxy or phenoxy; acyloxy such as acetyl, trifluoroacetylor benzoyl; hydroxy; amino or protonated amino; nitrate; phosphate;borate and the like. If appropriate these reactions may be carried outin the presence of a base such as triethylamine, pyridine or othertertiary amine, butyllithium, sodium tert-butoxide or similar, and/or acoupling reagent such as a carbodiimide.

When V is YR₂ where Y is --N═N--, or when V is Y* where Y* is a memberof the group ##STR98## the compound of formula (I) may be prepared asshown in Scheme 1 or Scheme 1a. In the Schemes and in the Examplesherein, the terms Me, Et, Pr, Ph and Bz signify methyl, ethyl, propyl,phenyl and benzyl respectively and the following additionalabbreviations are used:

THP tetrahydropyranyl,

t-Bu or But tertiary butyl

n-Bu n-butyl

iPr or Pr^(i) isopropyl

Hal halogen; i.e., fluorine, chlorine, bromine or iodine

Ts para-toluenesulfonyl

DMF dimethyl formamide

CDI N,N'-carbonyldiimidazole

BOP benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate

HBT 1-hydroxybenzotriazole

AcCN acetonitrile

DMSO dimethyl sulfoxide

Py.xSO₃ pyridine/sulfur trioxide complex

QC quinoline-2-carbonyl

PC 2-pyridinemethoxycarbonyl

MC N-morpholinocarbonyl

TMC N-thiomorpholinocarbonyl

Val valinyl

Asn asparaginyl

Ile isoleucyl

Gly glycinyl

Glu glutaminyl

Thr threonyl

Ala alanyl

(CN)Ala cyanoalanyl

(p-F)Bz 4-fluorobenzyl

(p-CN)Bz 4-cyanobenzyl

Z benzyloxycarbonyl

Boc t-butyloxycarbonyl

Ac acetyl

TFA trifluoroacetyl

C₆ H₁₁ cyclohexyl. ##STR99##

Other compounds of formula (I) may be prepared analogously, by reactinga synthon W--(A)_(n) --B--(A*)_(m) --Hal with HV, if appropriate in thepresence of a strong base. ##STR100## In Scheme 1a, R represents analkyl, aryl or aralkyl group, such as t-butyl, phenyl or benzyl.Suitable bases include pyridine, triethylamine and other tertiaryamines, alkali metal carbonates and alkali metal hydroxides. The moietyW--(A)_(n) --B--(A*)_(m) -- may be represented by R_(a), in which caseR_(b) represents R₅₀ as previously defined, and R_(c) represents R₂ aspreviously defined, or W--(A)_(n) --B--(A*)_(m) -- may be represented byR_(c), in which case R_(b) represents R₅, and R_(a) represents R₂.

When V is Y* where Y* is ##STR101## the compound of formula (I) may beprepared from by reacting a hydrazine wherein R₅₁ and R_(2*) are bothhydrogen, which may be prepared as shown in Scheme 1 or Scheme 1a, withan aldehyde or ketone.

When V is YR₂ where Y is the compound of formula ##STR102## (I) may beprepared as shown in Scheme 1b Scheme 1b ##STR103##

When V is YR₂ where Y is a member of the group ##STR104## the compoundof formula (I) may be synthesised by coupling a synthon W--(A)_(n)--B--(A*)_(m) -- Z_(a) with a synthon Z_(b), where Z_(a) includes one ofthe heteroatoms of Y, and Z_(b) includes the other heteroatom or atoms,as shown in schemes 2a and 2b: ##STR105##

Analogous methods may be used to obtain the correspondingthionophosphates and thionophosphonates.

When V is C(R₃₀)═Y** the compound of formula (I) may be prepared from asynthon having a ketone or aldehyde function, by condensation with asubstituted hydrazine or substituted hydroxylamine corresponding to Y**.

When V is Y*, where Y* is --N═O, the compound of formula (I) may beprepared by oxidising the corresponding primary amine, for example withCaro's acid, or H₂ O₂ in acetic acid, or H₂ O₂ with sodium tungstate. Itwill be appreciated that a compound of formula (I) wherein Y* is --N═Owill only be isolable as a nitroso compound when the carbon atom bearingY* has no α-hydrogens.

When V is Y*, where Y* is ##STR106## the compound of formula (I) may beprepared by oxidation of the corresponding thioether

    W--(A).sub.n --B--(A*).sub.m --S--R.sub.114*               (IV)

with hydrogen peroxide and acetic acid. The thioether (IV) may besynthesised by coupling a halide W--(A)_(n) --B--(A*)_(m) --Hal with athiol R_(114*) under basic conditions, or by reacting a disulfideR_(114*) SSR_(114*) with an organolithium reagent W--(A)_(n)--B--(A*)_(m) --Li derived from the corresponding halide.

When V is Y*, where Y* is ##STR107## the compound of formula (I) may beprepared by the Arbuzov reaction as shown in scheme 3: ##STR108##

The synthon W--(A)_(n) --B--(A*)_(m) --Z, where Z is any of thefunctional groups bound to (A*)_(m) which are represented in schemes 1to 3, may be prepared by coupling a suitably functionalised fragment W*with a correspondingly functionalised fragment Z*--(A)_(n) --B--(A*)_(m)--Z. Alternatively, the compound of formula (I) may be synthesised byfirst coupling V to (A)--_(n) --B--(A*)_(m) -- as described above withreference to schemes 1 to 3, and then coupling the resulting molecule toa functionalised fragment W*. Methods for coupling a precursor of groupW with a functionalised fragment Z*--(A)_(n) --B--(A*)_(m) --Z are wellknown in the art, and include methods analogous to those represented inschemes 1 to 3. For example, when W is R₁ X and X is Y, the coupling maybe achieved as described in schemes 1 to 3 above. When W is R₁ X and Xis NR₁₀, O or S, the coupling may be achieved by any of the knownmethods for the alkylation of amines, and the synthesis of ethers andthioethers, respectively. That is, the coupling may be achieved byreacting a fragment Z*--(A)_(n) --B--(A*)_(m) --Z wherein Z* is aleaving group such as halogen, sulfonate ester, acetate ortrialkylammonium salt, with R₁ R₁₀ NH, R₁ OH or R₁ SH, if necessary inthe presence of strong non-nucleophilic base such as butyllithium,sodamide or potassium tert-butoxide. Compounds in which X is S(O) orS(O)₂ may be prepared by the oxidation of the corresponding compound inwhich X is S. Compounds in which W is --CN, --C(R₅)═NR₃, --C(R₅)═NOR₃,--C(D)OR₃, --C(D)SR₃ or --C(D)NR₃ R₄ may be prepared from the fragmentZ*--(A)_(n) --B--(A*)_(m) --Z wherein Z* is an aldehyde, ketone orcarboxyl group as shown in Scheme 3a. ##STR109##

Compounds in which W is --N═CR₅ R_(5*) may be prepared by reacting thefragment Z*--(A)_(n) --B--(A*)_(m) --Z, where Z* is NH₂, with analdehyde or ketone having group(s) R₅ and R_(5*) bound to the carbonyl.

The fragment Z*--(A)_(n) --B--(A*)_(m) --Z may be prepared by methodswhich depend on the nature of B. Where B is a substituted carbon atom,the fragment may be conveniently prepared from a fragment E--C(O)--E*,in which E is a fragment Z*--(A)_(n) and E* is a fragment (A*)_(m) --Z,as shown in scheme 4: ##STR110##

Fragments ##STR111## which are starting materials for compounds offormula (I) are known compounds or analogs of known compounds which canbe prepared by methods analogous to methods used for preparation of theknown compounds. The synthesis of known fragments ##STR112## may befound with reference, for example, to Beilsteins Handbuch derOrganischen Chemie or to J. Buckingham, ed., Dictionary of OrganicCompounds 5th Edition (Chapman & Hall, New York, 1982). Alternatively, afunctionalised group E may be coupled to a group E*C(O)H, or afunctionalised group E* may be coupled to a group EC(O)H, followed byoxidation. For example, a halide EBr may be coupled to E*C(O)H with anorganolithium or organomagnesium reagent derived from EBr, followed byoxidation of the resulting secondary alcohol to the correspondingketone, if desired. Alternatively a carboxylic acid EC(O)OH may beconverted to an activated derivative, such as an ester or amide: forexample an amide obtained by reaction of the carboxylic acid withN,O-imethyl hydroxylamine hydrochloride in the presence of acarbodiimide and tertiary base, followed by addition of an organolithiumor organomagnesium reagent derived from E*Br, E*Cl or E*I.

When B is an epoxide of the type ##STR113## the fragment E--B--E* may beprepared from the corresponding olefin by reaction with a per-acid suchas trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid.Suitable olefins for conversion to the fragment E--B--E* arecommercially available or may be synthesised by known methods, forexample by means of the Wittig reaction or by an elimination reaction ofan alcohol, alcohol sulfonate, ester, halide or the like.

When B is a diol of the type ##STR114## the compound of formula (I) mayconveniently be prepared by reductive coupling of aldehydes EC(O)H andE*C(O)H as described in J. Org. Chem SS, 4506 (1990) and U.S. Pat. No.5,294,720.

When B is a heteroatom or substituted heteroatom, the fragmentZ*--(A)_(n) --B--(A*)_(m) --Z is a substituted amine, phosphine orphosphine oxide, or is an ether, thioether, sulfoxide or sulfone.Substituted amines, ethers, thioethers, sulfoxides and sulfones may beprepared as described above. Secondary or tertiary phosphines may beprepared by alkylation of the corresponding primary or secondaryphosphine as described, for example, in J. D. Roberts and M. C. Caserio,Basic Principles of Organic Chemistry (W. A. Benjamin, Inc., New York,1965).

In any of the reactions described above, it may be necessary to protectreactive group(s) in the compound of formula (I) other than thoseparticipating in a desired coupling or oxidation reaction using suitableprotecting group(s) in order to carry out the desired coupling oroxidation reaction without chemically affecting those reactive groups.Suitable protecting groups for this purpose are described in the worksof Greene and McOmie referenced above.

The compounds of formula (IB) wherein x and y are both 1 may be preparedas generally described above. A compound of formula (IB) which is##STR115## where R_(a) and R_(b) have the meaning of R₅₀, and R₅₀₆ aspreviously defined and R_(c) and R_(d) have the meaning of R₅₅₁ and R₅₀₂as previously defined, may be prepared from ethylene cyanohydrin by themethod shown in Scheme 5. ##STR116##

A substituted compound of formula (IB) may be prepared by the generalmethod of Scheme 5, with the substituents R₅₁₂, R₅₁₃, R₅₂₂, R₅₂₃, R₅₃₂,R₅₃₃, R₅₄₂, R₅₄₃ and R₅₅₀ being introduced, as desired, into thecompounds of formula (Va), (Vb), (Vc) and (Vd) shown in Scheme 5 by themethods illustrated in Scheme 5a. ##STR117##

In reaction 5a-1 shown above, it will be appreciated that the step ofintroducing the second substituent R' will only be carried out if it isdesired that both R₅₂₂ and R₅₂₃ be other than hydrogen. The reactionsshown in 5a-2 and 5a-3 may be repeated, if desired, so as to introduce asecond substituent on the carbon atom bearing R" or R"C(O). The secondsubstituent can be the same as or different from the first. Where one orboth of R₅₂₂ and R₅₂₃ is acyl, this group may be introduced as shown inreaction 5a-3 with respect to compound (Vb). Where R₅₂₂ and R₅₂₃ areboth hydrogen, the reactions shown in 5a-2 and 5a-3 may give mixtures ofproducts and in that case it may be preferable to introduce the desiredgroups R₅₃₂, R₅₄₃, R₅₄₂ and R₅₄₃ by replacing the ethylene bromohydrinshown in Scheme 5 with a suitably substituted bromohydrin obtained fromthe corresponding olefin as shown in Scheme 5b. It will be appreciatedthat the nature of the groups R₅₃₂, R₅₄₃, R₅₄₂ and R₅₄₃ will determinethe stereochemistry of the addition of HOBr to the olefin and of theopening of the epoxide. ##STR118##

Compounds of formula (IB) wherein B is other than --CH(OH)-- may beprepared by the methods shown in Scheme 4 after oxidation of thesecondary alcohol to the corresponding ketone.

The compounds of formula (IB) wherein B is a substituted carbon atom andy is 0 can be prepared by reacting a compound of formula (II), (IIA) or(IIB) ##STR119## wherein R_(14*), R₅₀₁, R₅₀₂, R₅₀₆, R₅₁₂, R₅₁₃, R₅₂₂,R₅₂₃, R₅₄₂ and R₅₄₃ have the significance given earlier and Hal is agroup selected from --Cl, --Br or --I, with a compound of formula (III)##STR120## wherein R₅₀₂, R₅₅₀ and R₅₅, have the significance givenearlier. Where a compound of formula (II) is used, the reaction may befollowed by oxidation of the resultant secondary alcohol to thecorresponding ketone. This ketone may be used for elaboration of thesubstituents on B as shown in Scheme 4.

A compound of formula (II), (IIA) or (IIB) may be prepared from aβ-amino acid or a β-amido acid as shown in Scheme 6. A compound offormula III may be prepared as shown in Scheme 1a. ##STR121##

An alternative route to the β-aminoaldehyde shown in Scheme 6 is byreduction of the methyl ester of the corresponding β-amino acids usingdiisobutylaluminium hydride.

β-amino acids, or β-amido acids, may conveniently be prepared by theMannich reaction of an amine or amide with an enolisable ketone in thepresence of formaldehyde or another aldehyde.

A compound of formula (IB) wherein x and y are both 0 may be prepared byreacting a compound of formula (IIC) or (IID) ##STR122## with a compoundof formula (III) as shown above. An analogous procedure, utilising aprimary or secondary amine rather than a hydrazine as shown in formula(II) yields a hydroxy diamine. A compound of formula (IIC) may beprepared from an α-amino acid by a method analogous to that shown inScheme 6, such as described in the following:

Evans, B. E., et al., J. Org. Chem., 50, 4615-4625 (1985);

Luly, J. R., et al., J. Org. Chem., 52, 1487-1492 (1987);

Handa, B. K., et al., European Patent Application No. 346,847-A2 (1989)and

Marshall, G. R., et al., International Patent Application No W091/08221.

Suitable α-amino acids may be prepared, for example, by the Streckersynthesis, starting from an appropriate ketone. The overall route to thecompound of formula (IIC) is shown in Scheme 7. Other suitable methodsare described in Coppola, et al. Asymmetric Synthesis. Construction ofChiral Molecules using Amino Acids (Wiley Interscience, New York, 1987).##STR123##

Where W is a nitrogen-containing group, and one of R₁ and R₁₀ is aprotected amino acid residue, the coupling of the protected amino acidresidue may be accomplished as shown in Scheme 8, in which the aminoacid (designated AA) protecting group is benzyloxycarbonyl, designatedZ. Methods for the formation of peptide bonds and for the protection ofpeptide residues are described, for example, in Gross and Meienhofer,eds., The Peptides, (Academic Press, New York, 1983). Suitable othercoupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) and diphenylphosphoryl azide (DPPA). ##STR124##

Numerous synthetic routes exist to substituted hydrazines, including thehydrazines of formula (III), useful in the synthesis of compounds offormula (I). The hydrazine intermediates (III) can be obtained usingknown methods such as those described in the following:

Dutta, A. S., et al., J. Chem. Soc. Perkin Trans. I, (1975) 1712-1720,

Ghali, N. I., et al., J. Org. Chem., 46, 5413-5414 (1981), Gante, J.,Synthesis (1989) 405-413 and

Houben-Weyl's Methoden der Organische Chemie, vol. 16a, Part 1, pp421-855; Georg Thieme Verlag, Stuttgart (1990)

Other methods for preparing substituted hydrazines are illustrated inScheme 9. ##STR125##

Compounds of formula (I) wherein a group selected from R₁, R_(1*), R₂,R_(2*), R₉, R₁₁, R₁₂, R₅₀ and R₅₁, together with another group selectedfrom R₁, R_(1*), R₂, R_(2*), R_(9*), R₁₀, R₁₁, R₁₂, R₅₀ and R₅₁ forms acyclic, bicyclic or fused ring system may be prepared by variants on theabove methods which will be readily apparent to persons skilled in theart in the light of the foregoing.

An example of a method of preparing one class of cyclic compounds offormula (I) is presented in Scheme 10: ##STR126##

Compounds in accordance with the present invention which do not includea solubilising group Px typically exhibit low to very low watersolubility. Inhibitors of HIV proteases which have hitherto beendescribed, and many other pharmaceutically or veterinarily activesubstances also typically exhibit low to very low water solubility. Thisproperty tends to cause the bioavailability of such substances to berelatively low. There is thus a need for a HIV protease inhibitor havingenhanced water solubility. Surprisingly, it has been found that theinclusion of a solubilising group Px as defined herein in a substancehaving low to very low water solubility results in enhancement of thewater solubility of the substance. Thus, substances in accordance withthe invention which include a solubilising group Px exhibit superiorbioavailability, including superior oral bioavailability, compared tocompounds in accordance with the invention which do not include asolubilising group Px.

Thus, according to a second embodiment of the present invention, thereis provided process for enhancing the water-solubility of apharmaceutical or veterinary substance, comprising derivatising afunctional group of said substance with a solubilising group Px, whereinPx is selected from the group consisting of Px*, ##STR127## wherein D is0 or S, R is H or C₁ -C₄ alkyl, and wherein Px* is selected from:##STR128## said functional group being capable of being derivatised withsaid solubilising group Px.

Generally, a compound according to the first embodiment includes atleast one solubilising group Px as defined above. More generally, asolubilising group in a compound of the first embodiment or in themethod of the second embodiment is selected from ##STR129##

Typically, a solubilising group is introduced into the molecule as thelast stage of its synthesis. For example, a solubilising group P(O)(OH)₂may be introduced to a free amino, hydroxy or mercapto group by reactionof the amino, hydroxy or mercapto group with dimethyl chlorophosphate,followed by mild hydrolysis to remove the methyl ester groups. Othersolubilising groups referred to above may be introduced by analogousmethods: that is, by reaction of an amino, hydroxy, mercapto or othergroup capable of being derivatised with a solubilising group, with areagent PxX', suitably protected if necessary (for example as methyl orbenzyl esters), wherein Px is as defined above and X' is a leaving groupsuch as Cl, Br, OH, OS(O)₂ R and the like, where R is C₁ -C₆ alkyl, forexample methyl, C₆ -C₁₀ aryl, for example phenyl or 4-methylphenyl, orC₇ -C₁₁ arylalkyl, for example benzyl. Alternatively, a solubilisinggroup P(O)(OH)₂ may be introduced to a free hydroxy group by reactionwith phosphorous acid and mercuric salts in the presence of a tertiaryamine, as described by Obata and Mukaiyama in J. Org. Chem., 32, 1063(1967). As a further alternative, an amino, hydroxyl or mercapto groupmay be reacted with phosphorous acid preferably in the presence of acoupling agent such as dicyclohexylcarbodiimide and pyridine to yield amolecule possessing the solubilising group --OP(O)(OH)H. Optionally,this group may be oxidised to the corresponding phosphate derivative,for example using bis(trimethylsilyl) peroxide (see Scheme 14 below foran illustration of this method). A further process for the introductionof a 1 group --P(O)(OH)₂ is described in Australian patent applicationno. 54311/86, and involves the reaction of an amino, hydroxy or mercaptogroup with certain diesters of amides of phosphorus acid, followed byoxidation and hydrolysis of the resulting intermediate compounds.

Suitable reagents for the introduction of a solubilising group --NO₂ arelower alkyl nitrates such as methyl nitrate or ethyl nitrate, and acylnitrates such as acetyl nitrate or benzoyl nitrate.

Other methods for the preparation of compounds of formulae (I) to (IAW)referred to herein are disclosed in U.S. Pat. Nos. 5,116,835, 5,126,326;5,132,400; 5,145,957; 5,198,426; 5,212,157; 5,215,968; 5,212,667;5,294,720; and 5,296,604; International Patent Application Nos.91/08221; 91/10442; 92/151319 and 92/21696; European Patent ApplicationNos. 0528242; 0519433 and 0432595 and Australian Patent Application Nos.35700/89; 53716/90; 63221/90; 71319/91; 71320/91; 71323/91; 82313/91;83206/91; 87594/91; 90531/91; 90851/94; 90925/91; 91251/91; 91332/91;18355/92; 26424/92; 37160/93; 38808/93 and 44930/93, the disclosures ofeach of which are incorporated herein by reference.

A third embodiment of the invention is directed to pharmaceuticalcompositions comprising a compound of formula (I) together with one ormore pharmaceutically acceptable carriers, diluents, adjuvants and/orexcipients.

In a fourth embodiment of the invention there is provided a method forinhibiting retroviral proteases in a mammal in need of such inhibition,comprising administering to the mammal an effective amount of a compoundof the first embodiment or of a composition of the second embodiment. Inone form of the third embodiment, there is provided a method for thetreatment or prophylaxis of HIV viral infections such as AIDS.

For inhibiting retroviral proteases or the treatment of HIV viralinfections, a composition of the second embodiment may be administeredorally, topically, parenterally, e.g. by injection and by intra-arterialinfusion, rectally or by inhalation spray.

For oral administration, the pharmaceutical composition may be in theform of tablets, lozenges, pills, troches, capsules, elixirs, powders,including lyophilised powders, solutions, granules, suspensions,emulsions, syrups and tinctures. Slow-release, or delayed-release, formsmay also be prepared, for example in the form of coated particles,multi-layer tablets or microgranules.

Solid forms for oral administration may contain pharmaceuticallyacceptable binders, sweeteners, disintegrating agents, diluents,flavourings, coating agents, preservatives, lubricants and/or time delayagents. Suitable binders include gum acacia, gelatin, corn starch, gumtragacanth, sodium alginate, carboxymethylcellulose or polyethyleneglycol. Suitable sweeteners include sucrose, lactose, glucose, aspartameor saccharine. Suitable disintegrating agents include corn starch,methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginicacid or agar. Suitable diluents include lactose, sorbitol, mannitol,dextrose, kaolin, cellulose, calcium carbonate, calcium silicate ordicalcium phosphate. Suitable flavouring agents include peppermint oil,oil of wintergreen, cherry, orange or raspberry flavouring. Suitablecoating agents include polymers or copolymers of acrylic acid and/ormethacrylic acid and/or their esters, waxes, fatty alcohols, zein,shellac or gluten. Suitable preservatives include sodium benzoate,vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propylparaben or sodium bisulphite. Suitable lubricants include magnesiumstearate, stearic acid, sodium oleate, sodium chloride or talc. Suitabletime delay agents include glyceryl monostearate or glyceryl distearate.

Liquid forms for oral administration may contain, in addition to theabove agents, a liquid carrier. Suitable liquid carriers include water,oils such as olive oil, peanut oil, sesame oil, sunflower oil, saffloweroil, arachis oil, coconut oil, liquid paraffin, ethylene glycol,propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol,glycerol, fatty alcohols, triglycerides or mixtures thereof.

Suspensions for oral administration may further comprise dispersingagents and/or suspending agents. Suitable suspending agents includesodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate orcetyl alcohol. Suitable dispersing agents include lecithin,polyoxyethylene esters of fatty acids such as stearic acid,polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate,polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate andthe like.

The emulsions for oral administration may further comprise one or moreemulsifying agents. Suitable emulsifying agents include dispersingagents as exemplified above or natural gums such as gum acacia or gumtragacanth.

For topical administration, the pharmaceutical composition may be in theform of a cream, ointment, gel, jelly, tincture, suspension or emulsion.The pharmaceutical composition may contain pharmaceutically acceptablebinders, diluents, disintegrating agents, preservatives, lubricants,dispersing agents, suspending agents and/or emulsifying agents asexemplified above.

For parenteral administration, the compound of formula I or its salt maybe prepared in sterile aqueous or oleaginous solution or suspension.Suitable non-toxic parenterally acceptable diluents or solvents includewater, Ringer's solution, isotonic salt solution, 5% dextrose in water,buffered sodium or ammonium acetate solution, 1,3-butanediol, ethanol,propylene glycol or polyethylene glycols in mixtures with water. Aqueoussolutions or suspensions may further comprise one or more bufferingagents. Suitable buffering agents include sodium acetate, sodiumcitrate, sodium borate or sodium tartrate, for example. Aqueoussolutions for parenteral administration are also suitable foradministration orally or by inhalation.

For rectal administration, the compound of formula I is suitablyadministered in the form of an enema or suppository. A suitablesuppository may be prepared by mixing the active substance with anon-irritating excipient which is solid at ordinary temperatures butwhich will melt in the rectum. Suitable such materials are cocoa butter,waxes, fats, glycerol, gelatin and polyethylene glycols. Suitable enemasmay comprise agents as exemplified above with reference to forms fortopical administration.

Suitably, an inhalation spray comprising a compound of formula I will bein the form of a solution, suspension or emulsion as exemplified above.The inhalation spray composition may further comprise an inhalablepropellant of low toxicity. Suitable propellants include carbon dioxideor nitrous oxide.

The dosage form of the compound of formula I will comprise from 0.01% to99% by weight of the active substance. Usually, dosage forms accordingto the invention will comprise from 0.1% to about 10% by weight of theactive substance.

The compound of formula I may be administered together or sequentiallywith one or more other active substances known or believed to haveanti-viral activity. Examples of such other active substances includeAZT, acyclovir, ddC, ddA, trisodium phosphonoformate, castanospermine,rifabutin, ribaviran, bropirimine, phosphonothioateoligodeoxynucleotides, dextran sulfate, α-interferon and ampligen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the transformation of the compound of Example5 ("Prodrug") into the compound of Example 20 of International PatentApplication No. PCT/AU93/00103 ("Drug") in rabbit's blood in vitro.

FIGS. 2 and 3 are graphs showing the transformation of Prodrug into Drugin vivo following intravenous and intramuscular (respectively)administration to a rabbit.

BEST MODE OF CARRYING OUT THE INVENTION

Methods for the preparation of compounds of formula (IB) wherein x and yare both 0, B is --CH(OH)-- and R₅₀₆, R₅₁₃, R₅₄₂ and R₅₄₃ are hydrogenare described in the following Schemes 11 and 12: ##STR130##

Scheme 13 presents an example of a method of preparation of Examples 11and 12, commencing with the product of Scheme 12 in which R₅₀₁ isbenzyloxycarbonyl, R₅₁₂ is methoxycarbonyl, R₅₅₀ and R₅₅₁ together forma 3,4-diazabicyclo 4.4.0!decane system and R₅₀₂ is tert-butoxycarbonyl:##STR131##

Scheme 14 presents an example of a method of preparation of compounds offormula shown in Table 4 below, in which the solubilising group Px isP(O)(OH)H or P(O)(OH)₂ : ##STR132##

Compositions of the third embodiment may be prepared by means known inthe art for the preparation of pharmaceutical compositions includingblending, grinding, homogenising, suspending, dissolving, emulsifying,dispersing and mixing of the compound of formula (1) together with theselected excipient(s), carrier(s), adjuvant(s) and/or diluent(s).

In the method for the treatment of HIV viral infections in accordancewith the fourth embodiment of the invention, a compound of the firstembodiment will usually be administered orally or by injection. Asuitable treatment may consist of the administration of a single dose ormultiple doses of the compound of formula (1) or of a composition of thethird embodiment. Usually, the treatment will consist of administeringfrom one to five doses daily of the compound of formula (I) for a periodof from one day to several years, up to the lifetime of the patient.Most usually, the treatment will consist of the administration of thecompound of formula (I) for a period of from one day to one year.

The administered dosage of the compound of formula I can vary anddepends on several factors, such as the condition of the patient.Dosages will range from 0.01 mg to 200 mg per kg. Usually, the dose ofthe active substance will be from 0.01 mg to 25 mg per kg of bodyweight.

Examples of dosage forms in accordance with the invention are asfollows:

1. Tablet

Compound of formula I 0.01 to 20 mg, generally 0.1 to 10 mg

Starch 10 to 20 mg

Lactose 100 to 250 mg

Gelatin 0 to 5 mg

Magnesium stearate 0 to 5 mg

2. Capsule

Compound of formula I 0.01 to 20 mg, generally 0.1 to 10 mg

Glycerol 100 to 200 mg

Distilled water 100 to 200 mg

Saccharin 0 to 2 mg

Methyl Paraben 1 to 2 mg

Polyvinylpyrrolidone 0 to 2 mg

3. Injectable solution

Compound of formula I 0.01 to 20 mg, generally 0.1 to 10 mg

Sodium chloride 8.5 mg

Potassium chloride 3 mg

Calcium chloride 4.8 mg

Water for injection, q.s. to 10 ml

4. Elixir

Compound of formula I 0.01 to 1 to 20 mg, generally 0.1 to 10 mg

Sucrose 100 mg

Glycerol 2ml

Carboxymethylcellulose 20mg

Cherry flavour 2 mg

Water q.s. to 10 ml

EXAMPLES

The following Examples describe the preparation of compounds accordingto the invention and are intended to illustrate the invention. TheExamples are not be construed as limiting in any way the scope of thepresent invention. Starting materials for the syntheses described in thefollowing Examples are described in International Patent Application No.PCT/AU93/00103. In these Examples, melting points were taken on a hotstage apparatus and are uncorrected. Proton and phosphorus NMR spectrawere recorded at 100 MHz or 300 MHz on Perkin Elmer R32 or Bruker EM 300spectrometers, respectively, in CDCl₃ unless otherwise stated. Chemicalshifts for proton NMR are ppm downfield from tetramethylsilane; chemicalshifts for P³¹ NMR are ppm downfield from1,2-bis(diphenylphosphino)ethane external standard. Thin layerchromotography (TLC) was performed on silica gel 60-F254 plates (Merck).Compounds were visualized by ultraviolet light and/or 2% aqueouspotassium permanganate solution. The composition (by volume) of the TLCsolvent systems were (A) hexane/ethyl acetate 3:2, and (B) concentratedNH₄ OH/isopropanol 1:3.

Example 14S,5S-5,6-Dibenzyl-1,2-(cis-1,2-cyclohexane)dimethyl-4-hydroxy-7-oxo-perhydro-1,2,6triazepine##STR133## Step A:4S,5S-5-benzyl-1,2-(cis-1,2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepine:Hydrogen chloride gas was bubbled through the solution of 0.51 g (1.26mmol) of cis-1,6-3-t-butoxycarbonyl4-(2S,3S)-2-hydroxy-3-amino4-phenylbutyl!-3,4-diazabicyclo 4.4.0!decane(isomer having R_(f) (A)=0.16 when eluted with 8% methanol indichloromethane) in 10 ml of 1% solution of methanol in methylenechloride for 30 min at room temperature. After purging the excess ofhydrogen chloride with nitrogen gas the solvent was removed underreduced pressure to give 0.42 g (100% yield) of the hydrochloride saltof cis-1,6-4- (2S,3S)-3-amino-2-hydroxy-4-phenylbutyl!-3,4-diaza-bicyclo4.4.0!decane as a hygroscopic, white solid. This was dissolved in 1 mlof dry DMF and 0.114 g (1.68 mmol) of imidazole and 0.21 g (1.38 mmol)of t-butyldimethylsilyl chloride were added under nitrogen. Theresulting mixture was stirred overnight at room temperature andevaporated to dryness in vacuo. The residue was diluted to 20 ml withethyl acetate, washed with saturated sodium bicarbonate and dried overanhydrous potassium carbonate and filtered off. The filtrate wasevaporated to dryness under reduced pressure and the residue wasdissolved in 20 ml of dry dioxane. To this, 0.204 g (1.26 mmol) of1,1'-carbonyldiimidazole was added and the resulting mixture was stirredfor 24 hrs at room temperature. After evaporation of the solvent underreduced pressure the residue was diluted to 15 ml with ethyl acetate andwashed with water (3×) and saturated aqueous sodium chloride solution,and then dried over anhydrous magnesium sulfate. Evaporation of thesolvent under reduced pressure and purification of the residue by columnchromatography (silica gel; hexane/ethyl acetate 3:2) gave 0.095 g (17%yield) of the title compound, melting at 145°-146° C.; R_(f) (A)═0.43;NMR 0.07, 0.09 (s,s 6H, CH₃); 0.94 (s, 9H, t-butyl CH₃); 1.2-2.0 (m,10H, cyclohexane CH₂, CH); 2.5-2.8 (m, 4H, CH₂ -3, benzyl CH₂); 3.2-3.7(m, 4H, dimethyl CH₂); 3.9-4.0 (m, 3H, CH4,5, NH); 7.1-7.32 (m, 5H,aromatic).

Step B: 4S,5S-5,6-dibenzyl-1,2-(cis-1,2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepine:##STR134##

4.5 mg (0.15 mmol) of 80% dispersion of sodium hydride in mineral oilwas added to a solution of 0.0665 g (0.15 mmol) of the product of Step Ain 0.2 ml of dry DMF at room temperature. After stirring for 30 min atroom temperature, 0.0179 ml (0.15 mmol) of benzyl bromide was thenadded. The resulting mixture was stirred overnight, then diluted to 15ml with ethyl acetate and washed with water, saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate.Evaporation of the solvent under reduced pressure and purification ofthe residue by column chromatography gave 0.029 g (36% yield) of thetitle compound as a heavy syrup; R_(f) (A)=0.77; NMR -0.35, -0.18 (s, s,CH₃); 0.8 (s, 9H, t-butyl CH₃); 1.2-2.2 (m, 1OH, cyclohexane CH₂, CH);2.56-4.18 (m, 12H, benzyl CH₂, dimethyl CH₂, CH₂ -3, CH-4,5); 6.8-7.4(m, 10H, aromatic).

Step C.4S,5S-5,6-Dibenzyl-1,2-(cis-1,2-cyclohexane)dimethyl-4-hydroxy-7-oxo-perhydro-1,2,-triazepine:

A mixture of 29 mg (0.0543 mmol) of the product of Step B and 0.0426 g(0.163 mmol) of tetrabutylammonium fluoride hydrate in 1 ml of anhydrousacetonitrile was stirred at 45°±5° C. for 3 hrs and evaporated todryness. The residue was purified by column chromatography (silica gel,hexane/ethyl acetate 3:2) to give 0.019 g (86% yield) of the titlecompound as a colourless foam; R_(f) (A)=0.26; NMR 1.2-2.1 (m, 18H,cyclohexane CH₂, CH, OH, 3.5×H₂ O); 2.6-4.0 (m, 1 1H, benzyl CH₂,dimethyl CH₂, CH₂ -3, CH-5); 4.83 (m, 1H, CH4); 7.0-7.4 (m, 10H,aromatic).

Example 24S,5S-1,5,6,Tribenzyl-2-isopropyl4-hydroxy-7-oxo-perhydro-1,2,6-triazepine

Step A:4S,5S-5-enzyl-2-isopropyl-4t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepine:

When t butyl 3-isopropyl-3-(2S,3S)-3-amino-2-hydroxy4-phenylbutyl!-carbazate was substituted forcis-1,6-3-t-butoxycarbonyl4-(2S,3S)-2-hydroxy-3-amino-phenylbutyl!-3,4-diazabicyclo 4.4.0!decane inStep A of Example 1 the identical process afforded the title compound in20% overall yield; melting point =131°-132° C. (hexane); R_(f) (A)=0.8;NMR 0.10, 0.11 (s, s, 6H, silyl CH₃); 0.95 (s, 9H, t-butyl CH₃);1.1-1.35 (m, 6H isopropyl CH₃); 2.8-3.2 (m, SH, CH₂ -3, CH-5, benzylCH₂); 3.45 (m, 1H, isopropyl H); 4.18 (m, 1H, CH-4); 4.41 (m, 1H NH-6);5.63 (s, 1H, NH-1); 7.1-7.4 (m, SH, aromatic).

Step B: 4S,5S-1,5,6tribenzyl-²-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,triazepine:

A mixture of 0.07 g (0.185 mmol) of the product of Step A and 0.012 g(0.371 mmol) of sodium hydride in 0.2 ml of dry DMF was stirred for 30min at room temperature, then 0.044 ml (0.371 mmol) of benzyl bromidewas added. The resulting mixture was stirred overnight and worked up asdescribed in Step B of Example 1. The purification of the crude productby column chromatography (silica gel, hexane/ethyl acetate 3:2) gave0.031 g (30% yield) of the title compound as a colourless syrup; Rf (A)=0.74, NMR -0.28, -0.22 (s,s, 6H, silyl CH₃); 0.8 (s, 9H, t-butyl CH₃);1.0-1.35 (m, 6H, isopropyl CH₃); 2.5-3.3 (m, 5H, CH₂₋₃, CH-5,5-benzylCH₂); 3.45-3.82 (m, 2H, isopropyl CH, CH-4); 4.0-5.38 (m, 4H, 1,6-benzylCH₂); 6.6-7.8 (m, 15H, aromatic).

Also, the fractions with Rf (A)=0.63 were combined and evaporated todryness under reduced pressure to give 0.061 g (70% yield) of4S,5S-5,6-dibenzyl-2-isopropyl4-t-butyl-dimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepineas a colourless solid; NMR 0.11 (d, 6H, silyl CH₃); 0.93 (s 9H, t-butylCH₃); 1.24 (m, 6H, isopropyl CH₃); 2.4-3.4 (m, 5H, CH₂ -3, CH-5,5-benzylCH₂); 3.75 (m, 1H, isopropyl CH); 4.0-4.7 (m, 3H, CH4, 6-benzyl CH₂);5.05 (m 1H, NH); 7.0-7.7 (m, 15H, aromatic).

Step C: 4S,5S-1,5,6 Tribenzyl-2-isopropyl-4-hydroxy-7-oxo-perhydro-1,2,6triazepine:

When the title compound of Step B was substituted for4S,5S-5,6-dibenzyl-1,2-(cis-1,2-cyclohexane)-dimethyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepinein Step C of Example 1, the identical process afforded the titlecompound with 98% yield as a foam; Rf (A)=0.68; NMR (CDCl₃) 1.07-1.19(d, d, 6H, isopropyl CH₃); 1.58 (s, 1H, OH); 2.6-3.15 (m, 5H, CH₂ -3,CH-5,5-benzyl CH₂); 3.2-5.3 (m, 6H, isopropyl CH, CH4,1,6-benzyl CH₂);6.8-7.6 (m, 15H, aromatic).

Example 34S,5S-5,6-dibenzyl-2-isopropyl4-hydroxy-7-oxo-perhydro-1,2,6-triazepine##STR135##

When4S,5S-5,6-2-isopropyl4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepinewas substituted for4S,5S-1,5,6-tribenzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1,2,6-triazepinein Step C of Example 2 the identical process afforded the title compoundin 88% yield; melting point=191°-193° C.; Rf (A)=0.17; NMR (DMSO-d₆, 80°C.) 2.5-3.0 (m, 4H, CH₂ -3,5-benzyl CH₂); 3.28 (m, 1H, CH-5); 3.6 (m,1H, CH-4); 3.8 (m, 1H, isopropyl CH); 4.2-4.7 (m, 3H, 6-benzyl CH₂ ;OH); 5.41 (m, 1H, NH); 7.0-7.4 (m, 10H, aromatic).

Example 4 t-Butyl 3-isopropyl-3- (2S,3S)-2-phosphitooxy-3-(N-quinaldoyl-L-paraginyl)amino-4-phenylbutylcarbazate ##STR136##

To a mixture of 0.4 g (0.67 mmol) of t-butyl 3-isopropyl-3- (2S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl carbazateand 0.12 g (1.47 mmol) of anhydrous phosphorous acid in 1.5 ml ofanhydrous pyridine was added 0.28 g (1.4 mmol) ofdicyclohexylcarbodiimide at room temperature under nitrogen, withstirring. After stirring for 2 hours at 60° C., the solvent wasevaporated under reduced pressure and the residue was treated with 28 mlof 0.1 ml aqueous sodium bicarbonate and vigorously stirred for 1 hourat room temperature. The precipitate was filtered off and washed withwater and the filtrate was acidified to pH˜1.5 with concentratedhydrochloric acid. The product was taken up b extraction with ethylacetate (3×50 ml), and the organic phase was dried over anhydrousmagnesium sulfate. Evaporation of the solvent gave 0.42 g (95% yield) ofthe title product as a colourless solid; Rf (B)=0.62; H¹ NMR (CDCl₃):1.08 (m, 6H, isopropyl CH₃); 1.41 (s, 9H, t-butyl CH₃); 2.7-4.8 (m, 14H,asn CH₂, butyl CH₂ -1,4; CH-2,3; isopropyl CH; P--OH×2H₂ O); 5.12 (m,1H, asn CH); 5.89 (s, 0.5 H, PH); 6.2-8.5 (m, 15.5H, aromatic, amide NH,0.5 PH); 9.02 m, 1H, asn NH); P³¹ NMR (CDCl₃) 14.99 (J_(P-H) =636 Hz).

Example 5 t-Butyl 3-isopropyl-3- (2S,3S)-2-phosphonooxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutylcarbazate ##STR137##

A suspension of 0.4 g (0.6 mmol) of the product of Example 4 in 2 ml ofhexamethyldisilazane was stirred for 45 min at 120°±5° C. At this pointthe reaction mixture became homogeneous. To this 0.3 ml ofbis(trimethylsilyl)peroxide (Cookson, P.G et al., J. Organomental.Chem., 1975, 92, C31) was added and stirring was continued for 1 hour atthe above temperature. The reaction mixture was cooled to roomtemperature, then evaporated to dryness in vacuo. The residue wasdissolved in 20 ml of methanol, evaporated to dryness under reducedpressure and redissolved in 12 ml of 0.1 ml aqueous sodium bicarbonate.The resulting mixture was acidified to pH˜1.5 with concentratedhydrochloric acid, saturated with sodium chloride and extracted withethyl acetate (3×50 ml). The combined organic phase was dried overanhydrous magnesium sulfate and evaporated to dryness to give 0.39 g(96% yield) of the title compound as a colourless solid; R_(f) (B)=0.07;H¹ NMR (CDCl₃): 1.2 (m, 6H, isopropyl CH₃); 1.4 (s, 9H, t-butyl CH₃);2.8-4.2 (m, 8H, asn CH₂ butyl CH₂ -1,4, CH-3, isopropyl CH); 4.2-6.4 (m,5H, asn CH, butyl CH-2, NH, POH); 6.5-8.4 (m, 14H, aromatic, NH); 8.78(m, 2H, NH); P³¹ NMR (CDCl₃) 9.6 (s).

Example 6 cis-1,6-3-t-Butoxcarbonyl4 (2S,3S)-2-phosphitooxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl!-3,4-diaza-bicyclo 4.4.0!decane ##STR138##

When cis-1,6-3-t-butoxycarbonyl-4- (2S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl!-3,4-diaza-bicyclo4.4.0!decane is substituted for t-butyl 3-isopropyl-3- (2S, 3)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl-carbazatein Example 4, the identical process affords the title compound in 89%yield, as a colourless solid; R_(f) (B)=0.64; H¹ NMR (CDCl₃): 1.1-1.8(m, 19H, t-butyl CH₃, decane CH₂ -7,8,9,10, CH-1,6); 2.12 (m, 1H, butylCH-3); 2.6-5.1 (m, 19H, asn CH₂, CH, butyl CH₂ -1,4, CH-2, decane CH₂-2,5, POH×2.5 H₂ O); 6.1-8.4 (m, 15H, amide NH, PH, aromatic); 9.08 (m,1H, asn NH); P³¹ NMR (CDCl₃) 16.43 (J_(PH) =700 Hz).

Example 7 cis-1,6-3-t-Butoxycarbonyl-4- (2S,3S)-2-phosphonooxy-3-N-quinaldoyl-L-asparaginyl)amino-4phenylbutyl!-3,4-diaza-bicyclo4.4.0!decane ##STR139##

When the product of Example 6 is substituted for t-butyl 3-isopropyl-3-(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutylcarbazate in Example 5, the identical process affords the title compoundin 83% yield, as a colourless solid; R_(f) (B)=0.12; H¹ NMR (CDCl₃):1.1-2.4 (m, 20H, t-butyl CH₃, decane CH₂ -7,8,9,10, CH-1,6, butyl CH-3);2.7-3.9 (m, 9H, asn CH₂, butyl CH₂ -1,4, CH-2, decane CH₂ -5); 5.1 (m,1H, asn CH); 6.1-8.3 (m, 21H, amide NH, aromatic, POH×2.5 H₂ O); 9.05.(m, 1H, asn NH); P³¹ NMR (CDCl₃) 10.5 (s).

Other representative compounds in accordance with the invention aredescribed in Tables 1 to 5. Other compounds in accordance with theinvention are substances in which a hydroxyl, amino or mercapto group isany of the compounds described in the Examples and disclosures of thefollowing, has been derivatised with a solubilising group Px as definedherein:

U.S. Pat. Nos. 5,116,835, 5,126,326; 5,132,400; 5,145,951; 5,198,426;5,212,157; 5,215,968; 5,221,667; 5,250563; 5,268,361; 5,294,720; and5,296,604; International Patent Application Nos. 90/09191; 91/08221;91/10442; 92/15319 and 92/21696; European Patent Application Nos.0574135; 0528242; 0519433 and 0432595 and Australian Patent ApplicationNos. 35700/89; 42308/89; 45665/89; 46115/89; 53716/90; 63221/90;66334/90; 71319/91; 71320/91; 71323/91; 77326/91; 81910/91; 82054/91;88900/91; 82313/91; 83234/91; 83206/91; 85877/91; 87309/91; 87409/91;87594/91; 15 88900/91; 89941/91; 90531/91; 90851/91; 90925/91; 91223/91;91251/91; 91332/91; 91790/92; 10812/92; 18355/92; 19373/92; 21944/92;22889/92; 24129/92; 24690/92; 26424/92; 31628/93; 35165/93; 35621/93;37160/93; 38808/93; 41230/93; 41659/93; 44930/93 and 49072/93, thedisclosures of each of which are incorporated herein by reference.

Example 8 In Vivo Removal of Phosphono Group

Solutions:

The product of Example 5 was converted quantitatively into thecorresponding disodium salt by treatment of the free acid with 2 equiv.of 0.2M sodium bicarbonate and lyophilization of the resulting solution.The stock solutions of the disodium salt of the product of Example 5,for blood and animal experiments, were prepared in sterile water.

Analyses:

Reverse phase analyses (HPLC) were performed on Waters ternary gradientliquid chromatograph equipped with 996 diode array detector set at 238nm. Separations were achieved on Alltima RP-18 (250×4.6 mm, i.d., 5μparticles), with the flow rate of 1 ml/min. The isocratic mobile phasecomposition used for analyses consisted of 40% of 0.1% aqueoustrifluoroacetic acid (TFA) and 60% of acetonitrile containing 0.1% TFAand 10% water. The retention time of the product of Example 5 (referredto below as "Prodrug") was in the range of 3.6-3.9 minutes and theretention time of t-butyl 3-isopropyl-3- (2S,3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino4-phenylbutyl-carbazate (referred to below as "Drug) was about 6.2 minutes. Detectorresponse was linear from 0.5 to 120 μM for Prodrug and 0.05 to 50 μM forDrug.

Standards and Sample Processing: The standards were prepared by serialdilution of Prodrug or Drug in rabbit blood collected into heparinisedtubes. Blood samples were transferred into vials containing 150 units ofheparin and stored on ice until processed. The blood samples were thenseparated by centrifuging at 6000 rpm for 10 min. The plasma sampleswere frozen and stored at -20° C. until they were analysed.

Plasma preparation for HPLC analysis: An equal volume (100 μL) of thawedplasma and acetonitrile was stirred with a vortex mixer and allowed tostand at room temperature for 5 minutes, then centrifuged at 14000 rpmfor 10 minutes. Samples of the supernantant (50 μL) were injected intothe chromatograph.

Transformation of Prodrug into Drug by Blood was established bymeasurement of prodrug and drug concentrations in plasma following theprodrug incubation in whole rabbit's blood (100 μM) at 36° C. for 19hours. FIG. 1 shows the concentrations of prodrug and drug under theseconditions over 19 hours.

Transformation of Prodrug into Drug after intravenous (IV)administration of prodrug (9.2 mg/kg) to rabbit was established bymeasurement of prodrug/drug concentrations in plasma over 120 min. Theformulated product, containing 30 mg/ml of prodrug, was well toleratedby the rabbit. The plasma profiles of prodrug and drug disappearance areshown in FIG. 2.

Transformation of Prodrug into Drug after Intramuscular (IM)administration of prodrug (7.9 mg/kg) to rabbit was established bymeasurement of drug concentrations in plasma over 330 min. Theformulated product, containing 30 mg/ml of prodrug was well tolerated bythe rabbit. The time dependence of the plasma concentration of the drugare shown in FIG. 3.

When prodrug was administered to a dog orally at a dose of 20mg/kg, theblood plasma concentration of drug was found to be 0.044, 0.141, 0.189,0.172, 0.164, 0.132, 0.089 and 0.060 μM, respectively, after 5, 15, 30,47, 63, 93, 124 and 155 minutes. When prodrug was administered to asecond dog orally at a dose of 10 mg/kg, the blood plasma concentrationof drug was found to be 0.137, 0.371, 0.297, 0.242, 0.176, 0.11, 0.071,and 0.050 μM, respectively, after 5, 15, 30, 45, 60, 94, 123 and 154minutes.

                                      TABLE 1    __________________________________________________________________________    Compounds of formula     ##STR140##    __________________________________________________________________________    Com-    pound    No. R.sub.501             R.sub.506    A          B    __________________________________________________________________________    9.  BzOC(O)               Et           CH.sub.2                                                       ##STR141##    10.         ##STR142##           Me           CH.sub.2                                                       ##STR143##         ##STR144##           H                                            ##STR145##                                                      CH(OH)         ##STR146##           H                                            ##STR147##                                                       ##STR148##         ##STR149##           EtO(CH.sub.2).sub.2                                           CH.sub.2 CF.sub.2                                                      CH(OAc)    14. Ac                    Ph           CH.sub.2 CH.sub.2                                                       ##STR150##    15. MeS(O)                iPr          CH.sub.2 CHF                                                       ##STR151##    16. MeS(O).sub.2          Pr           CH(Me)     CH(OTHP)    17. H                     BzOC(O)      C(Me).sub.2                                                       ##STR152##    18. Et                    Bz                                            ##STR153##                                                      CH(OH)    19. Et                    Bz                                            ##STR154##                                                       ##STR155##    20.         ##STR156##                               ##STR157##                                            ##STR158##                                                       ##STR159##         ##STR160##           Me           CH.sub.2 CCl.sub.2                                                       ##STR161##         ##STR162##           H.sub.2 NCH.sub.2 CH.sub.2                                           CH.sub.2 CHCl                                                      CH(OH)         ##STR163##           H.sub.2 NCH.sub.2 CH.sub.2                                           CH.sub.2 CHCl                                                       ##STR164##         ##STR165##           Me.sub.2 N   CH.sub.2 CF.sub.2                                                       ##STR166##    25. Ph                    n-Bu                                            ##STR167##                                                       ##STR168##    26. Me                               ##STR169##                                            ##STR170##                                                       ##STR171##         ##STR172##                               ##STR173##                                            ##STR174##                                                       ##STR175##         ##STR176##                               ##STR177##                                            ##STR178##                                                       ##STR179##         ##STR180##           BzC(O)                                            ##STR181##                                                       ##STR182##    30.         ##STR183##                               ##STR184##                                            ##STR185##                                                       ##STR186##         ##STR187##           t-BuOC(O)                                            ##STR188##                                                       ##STR189##    32  PhOC(O)               HOCH.sub.2 CH.sub.2                                            ##STR190##                                                       ##STR191##         ##STR192##           NCCH.sub.2 CH.sub.2                                            ##STR193##                                                       ##STR194##    34. H.sub.2 NC(O)         HOC(O)CH.sub.2                                            ##STR195##                                                      CH(OH)    35. H.sub.2 NC(O)         HOC(O)CH.sub.2                                            ##STR196##                                                       ##STR197##    36. MeOC(O)               MeOC(O)CH.sub.2                                            ##STR198##                                                      CH(OH)    37. MeOC(O)               MeOC(O)CH.sub.2                                            ##STR199##                                                       ##STR200##    38. Me.sub.2 NS(O).sub.2  Ph                                            ##STR201##                                                       ##STR202##    39. Me.sub.2 NS(O)        OMe                                            ##STR203##                                                       ##STR204##    40.         ##STR205##           Ac                                            ##STR206##                                                       ##STR207##    41. t-BuOC(O)             H                                            ##STR208##                                                       ##STR209##         ##STR210##           H                                            ##STR211##                                                      CH(OH)         ##STR212##           H                                            ##STR213##                                                      CH(OH)         ##STR214##           H                                            ##STR215##                                                      CH(OH)         ##STR216##           H                                            ##STR217##                                                      CH(OH)         ##STR218##           H                                            ##STR219##                                                      CH(OH)         ##STR220##           H                                            ##STR221##                                                      CH(OH)         ##STR222##           H                                            ##STR223##                                                      CH(OH)         ##STR224##           H                                            ##STR225##                                                       ##STR226##    50.         ##STR227##                               ##STR228##                                            ##STR229##                                                      CH(OH)    51. t-BuOC(O)             H                                            ##STR230##                                                      CH(OH)    52  t-BuOC(O)             H                                            ##STR231##                                                      CH(OH)    53. n-Pr                  n-Pr                                            ##STR232##                                                      CH(OH)         ##STR233##           H                                            ##STR234##                                                      CH(OH)         ##STR235##           H                                            ##STR236##                                                      CH(OH)         ##STR237##           H                                            ##STR238##                                                      CH(OH)         ##STR239##           H                                            ##STR240##                                                      CH(OH)    58. t-BuOC(O)             i-Bu                                            ##STR241##                                                       ##STR242##         ##STR243##                                            ##STR244##                                                       ##STR245##    60. t-BuOC(O)             H                                            ##STR246##                                                      CH(OH)    61. t-BuOC(O)             H                                            ##STR247##                                                      CH(OH)         ##STR248##           H                                            ##STR249##                                                       ##STR250##         ##STR251##           H                                            ##STR252##                                                       ##STR253##         ##STR254##           H                                            ##STR255##                                                       ##STR256##         ##STR257##           H                                            ##STR258##                                                       ##STR259##         ##STR260##           H                                            ##STR261##                                                       ##STR262##         ##STR263##           H                                            ##STR264##                                                       ##STR265##         ##STR266##           H                                            ##STR267##                                                       ##STR268##         ##STR269##           H                                            ##STR270##                                                       ##STR271##    70.         ##STR272##           H                                            ##STR273##                                                       ##STR274##         ##STR275##           H                                            ##STR276##                                                       ##STR277##         ##STR278##           H                                            ##STR279##                                                       ##STR280##         ##STR281##           H                                            ##STR282##                                                       ##STR283##         ##STR284##           H                                            ##STR285##                                                       ##STR286##         ##STR287##           H                                            ##STR288##                                                       ##STR289##         ##STR290##           H                                            ##STR291##                                                       ##STR292##         ##STR293##           H                                            ##STR294##                                                       ##STR295##         ##STR296##                               ##STR297##                                            ##STR298##                                                      CH(OH)         ##STR299##                               ##STR300##                                            ##STR301##                                                       ##STR302##    80.         ##STR303##                               ##STR304##                                            ##STR305##                                                       ##STR306##         ##STR307##           H                                            ##STR308##                                                       ##STR309##         ##STR310##           H                                            ##STR311##                                                       ##STR312##         ##STR313##           H                                            ##STR314##                                                       ##STR315##         ##STR316##           H                                            ##STR317##                                                       ##STR318##         ##STR319##           H                                            ##STR320##                                                       ##STR321##         ##STR322##           H                                            ##STR323##                                                       ##STR324##         ##STR325##           H                                            ##STR326##                                                       ##STR327##         ##STR328##           H                                            ##STR329##                                                      CH(OH)         ##STR330##           H                                            ##STR331##                                                       ##STR332##    90.         ##STR333##           H                                            ##STR334##                                                       ##STR335##         ##STR336##           H                                            ##STR337##                                                       ##STR338##         ##STR339##           H                                            ##STR340##                                                      CH(OH)         ##STR341##           H                                            ##STR342##                                                       ##STR343##         ##STR344##           H                                            ##STR345##                                                       ##STR346##         ##STR347##           H                                            ##STR348##                                                      CH(OH)         ##STR349##           H                                            ##STR350##                                                      CH(OH)         ##STR351##           H                                            ##STR352##                                                      CH(OH)         ##STR353##           H                                            ##STR354##                                                      CH(OH)         ##STR355##           H                                            ##STR356##                                                       ##STR357##    100.         ##STR358##           H                                            ##STR359##                                                       ##STR360##    101.         ##STR361##           H                                            ##STR362##                                                       ##STR363##    102.         ##STR364##           H                                            ##STR365##                                                       ##STR366##    103.         ##STR367##           H                                            ##STR368##                                                      CH(OH)    104.         ##STR369##           H                                            ##STR370##                                                       ##STR371##    105.         ##STR372##           H                                            ##STR373##                                                       ##STR374##    106.         ##STR375##           H                                            ##STR376##                                                       ##STR377##    107.         ##STR378##           H                                            ##STR379##                                                      CH(OH)    108.         ##STR380##           PhCO         CH(OH)     CH(OH)    109.         ##STR381##                               ##STR382##                                            ##STR383##                                                      CH(OH)    __________________________________________________________________________    Com-    pound    No. A*           R.sub.550  R.sub.551   R.sub.502    __________________________________________________________________________    9.  CH.sub.2     (CH.sub.2).sub.4       t-BuOC(O)    10. CH.sub.2     Et         H           SO.sub.2 Me    11. CH.sub.2                      ##STR384##            t-BuOC(O)    12. CH.sub.2                      ##STR385##            t-BuOC(O)    13. CF.sub.2 CH.sub.2                     H          Me          Ac         ##STR386##  CO.sub.2 Me                                Pr          H    15. CHFCH.sub.2  Me         Bz          S(O).sub.2 Ph         ##STR387##                      ##STR388##            BzC(O)    17. C(Me).sub.2                      ##STR389##                                             ##STR390##         ##STR391##                      ##STR392##            S(O)Me         ##STR393##                      ##STR394##            S(O)Me    20. CH(Me)       i-Pr       i-Pr        H    21. CCl.sub.2 CH.sub.2                      ##STR395##                                             ##STR396##         ##STR397##  Bz                     (CH.sub.2).sub.3 C(O)         ##STR398##  Bz                     (CH.sub.2).sub.3 C(O)    24. CF.sub.2 CH.sub.2                      ##STR399##                                             ##STR400##         ##STR401##  Ph                                             ##STR402##    26. C(Et).sub.2                      ##STR403##            Me         ##STR404##                      ##STR405##            S(O).sub.2 NMe.sub.2         ##STR406##  CH.sub.2 CH.sub.2 C(O) S(O).sub.2 Ph         ##STR407##  Ac         Ac          Et    30.         ##STR408##  MeOCH.sub.2 CH.sub.2                                Ph                                             ##STR409##         ##STR410##                      ##STR411##                                             ##STR412##         ##STR413##                      ##STR414##                                             ##STR415##         ##STR416##                      ##STR417##            n-Bu         ##STR418##                      ##STR419##            n-Pr         ##STR420##                      ##STR421##            n-Pr         ##STR422##  (CH.sub.2).sub.3       MeOC(O)         ##STR423##  (CH.sub.2).sub.3       MeOC(O)         ##STR424##                      ##STR425##                                             ##STR426##         ##STR427##  S(O)NMe.sub.2                                S(O)NMe.sub.2                                             ##STR428##    40.         ##STR429##                      ##STR430##                                 ##STR431## S(O).sub.2 OCH.sub.3    41. CH.sub.2     Bz         H           t-BuOC(O)    42. CH(Et)                      ##STR432##                                             ##STR433##    43. CH.sub.2                      ##STR434##                                             ##STR435##    44. CH.sub.2                      ##STR436##                                             ##STR437##    45. CH.sub.2                      ##STR438##                                             ##STR439##    46. CH.sub.2                      ##STR440##            S(O).sub.2 OBz    47. CH.sub.2                      ##STR441##            S(O)OBu.sup.t    48. CH.sub.2                      ##STR442##            S(O).sub.2 NH.sub.2    49. CH(Et)                      ##STR443##                                             ##STR444##    50. CH.sub.2     Bz         H           t-BuOC(O)    51. CH.sub.2                      ##STR445##                                H           t-BuOC(O)    52. CH.sub.2                      ##STR446##                                 ##STR447## t-BuOC(O)    53. CH.sub.2                      ##STR448##                                             ##STR449##    54. CH.sub.2                      ##STR450##                                             ##STR451##    55. CH.sub.2                      ##STR452##                                             ##STR453##         ##STR454##  H          H                                             ##STR455##         ##STR456##  H          H                                             ##STR457##    58. CH.sub.2                      ##STR458##                                H                                             ##STR459##    59. CH(i-Pr)                      ##STR460##                                             ##STR461##    60. CH.sub.2                      ##STR462##                                             ##STR463##    61. CH.sub.2                      ##STR464##                                             ##STR465##    62. CH.sub.2     Bz         H           BzOC(O)    63. CH.sub.2     Bz         H                                             ##STR466##    64. CH.sub.2     Bz         H                                             ##STR467##    65. CH.sub.2     Bz         H                                             ##STR468##    66. CH.sub.2     Bz         H                                             ##STR469##    67. CH.sub.2     Bz         H                                             ##STR470##    68. CH.sub.2     Bz         H                                             ##STR471##    69. CH.sub.2     Bz         H                                             ##STR472##    70. CH.sub.2     Bz         H                                             ##STR473##    71. CH.sub.2     Bz         H                                             ##STR474##    72. CH.sub.2     Bz         H                                             ##STR475##    73. CH.sub.2     Bz         H                                             ##STR476##    74. CH.sub.2     Bz         H                                             ##STR477##    75. CH.sub.2     Bz         H                                             ##STR478##    76. CH.sub.2     Bz         H                                             ##STR479##    77. CH.sub.2     Bz         H                                             ##STR480##    78. CH.sub.2                      ##STR481##                                             ##STR482##    79. CH.sub.2                      ##STR483##                                             ##STR484##    80.         ##STR485##                      ##STR486##                                             ##STR487##    81. CH.sub.2     Bz         H                                             ##STR488##    82. CH.sub.2     Bz         H                                             ##STR489##    83. CH.sub.2     Bz         H                                             ##STR490##    84. CH.sub.2     i-Pr       H           t-BuOC(O)    85. CH.sub.2     i-Pr       H           t-BuOC(O)    86. CH.sub.2     i-Pr       H           t-BuOC(O)    87. CH.sub.2     Bz         H                                             ##STR491##    88. CH.sub.2     Bz         H           t-BuOC(O)    89. CH.sub.2     Bz         H           t-BuOC(O)    90. CH.sub.2                      ##STR492##                                H           t-BuOC(O)    91. CH.sub.2                      ##STR493##                                H           t-BuOC(O)    92. CH.sub.2     CH.sub.2 CF.sub.3                                H           t-BuOC(O)    93. CH.sub.2     CH.sub.2 CF.sub.3                                H           t-BuOC(O)    94. CH.sub.2                      ##STR494##            t-BuOC(O)    95. CH.sub.2                      ##STR495##            i-Pr    96. CH.sub.2                      ##STR496##            i-Pr    97. CH.sub.2                      ##STR497##            t-BuOC(O)    98. CH.sub.2                      ##STR498##            t-BuOC(O)    99. CH.sub.2     Bz         H           t-BuOC(O)    100.        CH.sub.2     Bz         H           t-BuOC(O)    101.        CH.sub.2                      ##STR499##                                H           t-BuOC(O)    102.        CH.sub.2                      ##STR500##                                H           t-BuOC(O)    103.        CH.sub.2     i-Pr       H                                             ##STR501##    104.        CH.sub.2     i-Pr       H           t-BuOC(O)    105.        CH.sub.2     i-Pr       H           t-BuOC(O)    106.         ##STR502##                      ##STR503##                                             ##STR504##    107.        CH.sub.2                      ##STR505##            BzOC(O)    108.        CH(OH)                      ##STR506##            C(O)SMe    109.         ##STR507##                      ##STR508##                                             ##STR509##    __________________________________________________________________________

    TABLE 2      - Compound of formula W(A).sub.nB(A*).sub.mV      Compound      No W (A).sub.n B (A*).sub.m V      110.      ##STR510##      ##STR511##      ##STR512##      CH.sub.2      ##STR513##     111.      ##STR514##      --      ##STR515##      CH.sub.2      ##STR516##     112.      ##STR517##      ##STR518##      CH(OH)      ##STR519##      ##STR520##     113.      ##STR521##      CH.sub.2CH.sub.2CH.sub.2      ##STR522##      ##STR523##      NNPh     114.      ##STR524##      ##STR525##      CH(NH.sub.2)      ##STR526##      ##STR527##     115.      ##STR528##      ##STR529##      ##STR530##      ##STR531##      ##STR532##     116. PhC(O)NH      ##STR533##      ##STR534##      C(O)CH.sub.2      ##STR535##     117.      ##STR536##      CH.sub.2CH.sub.2 O CH.sub.2CH.sub.2      ##STR537##     118.      ##STR538##      ##STR539##      NH      ##STR540##      ##STR541##     119.      ##STR542##      ##STR543##      ##STR544##      CH.sub.2      ##STR545##     120.      ##STR546##      ##STR547##      ##STR548##      CH.sub.2      ##STR549##     121.      ##STR550##      ##STR551##      ##STR552##      CH.sub.2      ##STR553##     122. CN (CH.sub.2).sub.2 O(CH.sub.2).sub.2      O     ##STR554##      CH.sub.2      CH.sub.2     ##STR555##     123. MeOC(O) CH.sub.2      CH.sub.2     ##STR556##      O(CH.sub.2).sub.2      O(CH.sub.2).sub.2     ##STR557##     124. CN      ##STR558##      ##STR559##      CH.sub.2      CH.sub.2     ##STR560##     125.      ##STR561##      O (CH.sub.2).sub.2 CH(Me) OS(O).sub.2 CH.sub.2      Ph                                                    126.      ##STR562##      ##STR563##      ##STR564##      CH.sub.2      ##STR565##     127.      ##STR566##      ##STR567##      ##STR568##      CHCH      ##STR569##     128.      ##STR570##      ##STR571##      ##STR572##      CHCH      ##STR573##     129.      ##STR574##      ##STR575##      ##STR576##      ##STR577##      ##STR578##     130.      ##STR579##      ##STR580##      ##STR581##      ##STR582##      ##STR583##     131.      ##STR584##      ##STR585##      ##STR586##      ##STR587##      ##STR588##     132.      ##STR589##      ##STR590##      ##STR591##      CH.sub.2      ##STR592##     133.      ##STR593##      ##STR594##      ##STR595##      --      ##STR596##     134.      ##STR597##      ##STR598##      ##STR599##      CH.sub.2      ##STR600##     135.      ##STR601##      ##STR602##      ##STR603##      CH.sub.2      ##STR604##     136.      ##STR605##      ##STR606##      S(O).sub.2      ##STR607##      S(O).sub.2      NMe.sub.2                137.      ##STR608##      ##STR609##      CH(OH) CH.sub.2      ##STR610##     138.      ##STR611##      ##STR612##      CH(OH)      ##STR613##      ##STR614##     139.      ##STR615##      ##STR616##      CH(OH) CH.sub.2      ##STR617##     140.      ##STR618##      CH.sub.2      CH.sub.2     ##STR619##      CH.sub.2      CH.sub.2     ##STR620##     ##STR621##

    TABLE 4      - Compounds of formula                                                                              C     ompound      No. R.sub.501 R.sub.506 R.sub.12 Px R.sub.550 R.sub.551 R.sub.502      182. Z H Bz P(O)(OH).sub.2 i-Pr H Boc      183. Z H Bz P(S)(OH).sub.2      ##STR622##      Boc     184. Z H Bz P(O)(OH).sub.2      ##STR623##      Boc     185. Z H Bz P(O)(OH).sub.2      ##STR624##      Boc                                                                              1     86. Z H Bz HP(O)(OH) i-Pr H C(O)Bu.sup.t      187. Z H Bz HP(O)(OH) Bz H Boc     188. Z H Bz      ##STR625##      C.sub.6      H.sub.11 H Boc            189. Z H Bz P(O)(OH).sub.2 (CH.sub.2).sub.4 Boc      190. Z H Bz      ##STR626##      i-Pr H Z     191. ZVal H Bz      ##STR627##      Bz H ZVal     192. ZVal H Bz      ##STR628##      CH.sub.2 C.sub.6      H.sub.11 H ZVal                      193. ZVal H Bz      ##STR629##      (p-F)Bz H Boc     194. ZVal H Bz      ##STR630##      (p-F)Bz H Boc--Val     195. ZVal H Bz      ##STR631##      (p-F)Bz H Val     196. ZVal H Bz      ##STR632##      (p-F)Bz H MCGlyVal     197. ZVal H (p-F)Bz      ##STR633##      (p-F)Bz H Boc     198. ZVal H (p-F)Bz      ##STR634##      (p-F)Bz H H     199. ZVal H (p-F)Bz      ##STR635##      (p-F)Bz H      ##STR636##     200. ZVal H (p-F)Bz      ##STR637##      (p-F)Bz H      ##STR638##     201. ZVal H Bz      ##STR639##      CH.sub.2 C.sub.6      H.sub.11 H TMCVal                      202. ZVal H Bz      ##STR640##      (p-F)Bz H ZVal     203. ZVal H Bz      ##STR641##      (p-CN)Bz H ZVal     204. ZVal H Bz      ##STR642##      ##STR643##      H      ##STR644##     205. ZVal H Bz      ##STR645##      n-Bu H      ##STR646##     206. ZVal H Bz      ##STR647##      n-Bu H      ##STR648##     207. ZVal H Bz      ##STR649##      n-Bu H      ##STR650##     208. ZVal H Bz P(O)(OH).sub.2 (p-F)Bz H      ##STR651##     209. ZVal H (p-F)Bz      ##STR652##      (p-F)Bz H      ##STR653##     210. ZVal H (p-F)Bz      ##STR654##      (p-F)Bz H      ##STR655##     211. ZVal H (p-F)Bz P(O)(OH).sub.2 (p-F)Bz H MCGlyVal      212. ZAsn H Bz P(O)(OH).sub.2 (p-F)Bz H Boc      213. ZAsn H Bz P(O)(OH).sub.2 (p-F)Bz H ZVal      214. ZAsn H Bz P(O)(OH).sub.2 Bz H Boc     215. Z-Ile H Bz P(S)(OH).sub.2      ##STR656##      H Z-Ile     216. ZGlu H Bz      ##STR657##      (p-F)Bz H ZGlu     217. QCVal H Bz P(O)(OH).sub.2 i-Pr H Boc      218. QCVal H Bz P(O)(OH).sub.2      ##STR658##      Boc                                                                              2     19. QCVal H Bz HP(O)(OH) Bz H QCVal      220. QCAsn H Bz HP(O)(OH) i-Pr H Boc     221. QCAsn H Bz P(O)(OH).sub.2 i-Pr H      ##STR659##     222. QCAsn H Bz HP(O)(OH) i-Pr H      ##STR660##     223. QCAsn H Bz P(O)(OH).sub.2 i-Pr H Boc      224. QCAsn H Bz P(O)(OH).sub.2 i-Pr H QCVal     225. QCAsn H Bz      ##STR661##      ##STR662##      H Boc      226. QCAsn H Bz P(O)(OH).sub.2      ##STR663##      Boc     227. QCAsn H Bz      ##STR664##      ##STR665##      Boc      228. QCAsn H Bz      ##STR666##      i-Pr H C(O)Bu.sup.t     229. QCAsn H Bz P(O)(OH).sub.2 i-Pr H C(O)NHBu.sup.t      230. QCAsn H Bz P(O)(OH).sub.2 Bz H Boc      231. QCAsn H Bz P(O)(OH).sub.2 C.sub.6      H.sub.11 H Boc                    232. QCAsn H Bz P(O)(OH).sub.2     (CH.sub.2).sub.4 Boc      233. QCAsn H Bz      ##STR667##      (p-F)Bz H Boc     234. QCAsn H (p-F)Bz      ##STR668##      Bz H QCVal      235. QCAsn H Bz P(O)(OH).sub.2      ##STR669##      Boc     236. QCThr H Bz P(O)(OH).sub.2      ##STR670##      Boc     237. QC(CN)Ala H Bz P(O)(OH).sub.2      ##STR671##      Boc      238. BzC(O) H Bz P(O)(OH).sub.2      ##STR672##      H Boc     239. BzC(O)Val H Bz P(O)(OH).sub.2 Bz H BzC(O)Val      240. PCVal H Bz P(O)(OH).sub.2      ##STR673##      Boc     241. PCVal H Bz P(O)(OH).sub.2      ##STR674##      Boc     242. PCVal H Bz P(O)(OH).sub.2      ##STR675##      ##STR676##                                                                              2     43. PCVal H Bz P(O)(OH).sub.2 Bz H PCVal      244. PCVal H Bz P(O)(OH).sub.2 i-Pr H PCVal      245. PCVal H Bz P(O)(OH).sub.2 CH.sub.2 C.sub.6 H.sub.11 H PCVal             246. PCAsn H Bz P(O)(OH).sub.2 i-Pr H Boc      247. H H Bz P(O)(OH).sub.2      ##STR677##      Boc                                                                              2     48. Val H Bz P(O)(OH).sub.2 Bz H Val      249. Val H Bz P(O)(OH).sub.2 CH.sub.2 C.sub.6      H.sub.11 H Val                                                   250. Val H Bz P(O)(OH).sub.     2      ##STR678##      H Val     251. Boc H Bz P(O)(OH).sub.2 Bz H Boc      252. Boc H Bz S(O).sub.2 OH CH.sub.2 C.sub.6      H.sub.11 H Boc              253. Boc H Bz B(OH).sub.2 i-Pr H Boc             254. BocVal H Bz S(O).sub.2 OH CH.sub.2 C.sub.6 H.sub.11 H     BocVal     255. BocVal H Bz P(O)(OH).sub.2      ##STR679##      H BocVal     256. BocVal H Bz P(O)(OH).sub.2 Bz H BocVal      257. MCVal H Bz P(O)(OH).sub.2 Bz H MCVal      258. MCVal H Bz S(O).sub.2      OH (p-F)Bz H Boc                              259. MCVal H Bz S(O).sub.2      OH (p-F)Bz H ZVal      260. MCVal H Bz P(O)(OH).sub.2 (p-F)Bz H Val     261. MCVal H Bz      ##STR680##      (p-F)Bz H      ##STR681##     262. MCVal H Bz NO.sub.2 i-Pr H      ##STR682##     263. MCVal H (p-F)Bz      ##STR683##      (p-F)Bz H MCVal     264. TMCVal H Bz      ##STR684##      Bz H TMCVal     265. TMCVal H Bz      ##STR685##      i-Pr H TMCVal     266. Asn H Bz      ##STR686##      (p-P)Bz H Boc     267. TFA H Bz      ##STR687##      (p-F)Bz H Boc     268. TFA H Bz      ##STR688##      (p-F)Bz H ZVal     269. TFAVal H Bz      ##STR689##      i-Pr H      ##STR690##     270. AcVal H Bz P(O)(OH).sub.2 Bz H Ac      271. AcVal H Bz P(O)(OH).sub.2 CH.sub.2 C.sub.6 H.sub.11 H AcVal             272. AcVal H Bz P(O)(OH).sub.2 (p-F)Bz H AcVal      273. AcVal H Bz P(O)(OH).sub.2 (p-CN)Bz H AcVal      274. AcVal H Bz P(O)(OH).sub.2 i-Pr H AcVal     275. AcVal H Bz      ##STR691##      i-Pr H      ##STR692##     276. Ac-IIe H Bz P(O)(OH).sub.2 CH.sub.2 C.sub.6 H.sub.11 H AcIle             277. PhC(O)NHAsn H Bz P(O)(OH).sub.2 i-Pr H Boc     278.      ##STR693##      H Bz P(O)(OH).sub.2 i-Pr H Boc     279.      ##STR694##      H Bz P(O)(OH).sub.2 i-Pr H Boc     280.      ##STR695##      H Bz P(O)(OH).sub.2 i-Pr H Boc      281. CH.sub.3 OC(O)Val H Bz P(O)(OH).sub.2 i-Pr H CH.sub.3 OC(O)Val                                                                          282     CH.sub.3      OC(O)Val H Bz     ##STR696##      (p-F)Bz H CH.sub.3      OC(O)Val                        283 CH.sub.3      OC(O)Val H Bz     ##STR697##      (p-CN)Bz H CH.sub.3      OC(O)Val                         284.      ##STR698##      H Bz      ##STR699##      (p-F)Bz H      ##STR700##     285.      ##STR701##      H Bz      ##STR702##      i-Pr H      ##STR703##     286.      ##STR704##      H (p-F)Bz      ##STR705##      Bz H      ##STR706##     287.      ##STR707##      H Bz      ##STR708##      i-Pr H      ##STR709##     288.      ##STR710##      H CH.sub.2 C.sub.6      H.sub.11     ##STR711##      i-Pr H      ##STR712##     289. MeSO.sub.2 H Bz      ##STR713##      Bz H BzC(O)Val     290.      ##STR714##      H Bz      ##STR715##      n-Bu H      ##STR716##     291. Z H Bz P(O)(OH).sub.2      ##STR717##      H Boc      292. QCGlu H Bz P(O)(OH).sub.2      ##STR718##      Boc     293. ZAsn H Bz P(O)(OH).sub.2 i-Pr Boc

                                      TABLE 5    __________________________________________________________________________    Further examples of compounds of formula (I)    __________________________________________________________________________    294.        ##STR719##    295.        ##STR720##    296.        ##STR721##    297.        ##STR722##    298.        ##STR723##    299.        ##STR724##    300.        ##STR725##    301.        ##STR726##    302.        ##STR727##    303.        ##STR728##    304.        ##STR729##    305.        ##STR730##    306.        ##STR731##    307.        ##STR732##    308.        ##STR733##    309.        ##STR734##    310.        ##STR735##    311.        ##STR736##    312.        ##STR737##    313.        ##STR738##    314.        ##STR739##    315.        ##STR740##    316.        ##STR741##    317.        ##STR742##    __________________________________________________________________________

I claim:
 1. A compound according to the formula (I) or apharmaceutically acceptable salt or prodrug thereof:

    W--(A).sub.n --B--(A*).sub.m --V                           (I)

wherein n and m are both 1 B is ##STR743## wherein R_(14*) is hydrogenand M is OR₁₅ wherein R₁₅ is a group Px; Px is a solubilizing groupwhich is labile in vivo; V is a group ##STR744## wherein R_(2*) isselected from the group consisting of optionally substituted (C₁-C₁₈)acyl and C(O)OR₂₁ wherein R₂₁ is selected from hydrogen and R₂₀,and wherein R₂₀ is selected from the group consisting ofoptionallysubstituted (C₁ -C₁₂)alkyl, optionally substituted (C₂ -C₁₂)alkenyl,optionally substituted (C₂ -C₁₂)alkynyl, optionally substituted (C₃-C₁₂)cycloalkyl, optionally substituted (C₃ -C₁₂)cycloalkyl (C₁-C₆)alkyl, optionally substituted (C₆ -C₁₂)aryl, optionally substituted(C₆ -C₁₂)aryl(C₁ -C₄)alkyl, optionally substituted (C₆ -C₁₂)acyl, andoptionally substituted heterocyclic R₅₀ and R51 are independentlyselected from and R₂₀ are previously defined, A and A* are ##STR745##wherein L is a bond, R₁₃ is hydrogen and each R₁₂ independently isselected from the group consisting of hydrogen and R₂₀ as previouslydefined; and W is R_(1*) X*, wherein R_(1*) is selected from the grouprepresented by the formula R₄₀₁ NHCH(R₄₀₀)C(O)-- wherein R₄₀₀ is theside chain of a naturally occurring amino acid and R₄₀₁ usquinoline-2-carbonyl; and X* is NR₁₀ wherein R₁₀ is selected fromhydrogen and R₂₀ as previously defined.
 2. A compound according to claim1, wherein Px is selected from the group consisting of Px*, ##STR746##wherein D is O or S, R is H or C₁ -C₄ alkyl, and wherein Px* is selectedfrom: ##STR747## wherein X═O,S,S(O),S(O)₂ ; ##STR748## wherein R' hasthe meaning of R.
 3. A compound according to claim 2 wherein Px* isselected from the group consisting of ##STR749##
 4. A compound accordingto claim 1 selected from the group consisting of derivatives of:(i)t-butyl-3-isopropyl-3- (2orS,3S)-2-hydroxy-3-(N-quinaldyl-L-valyl)-amino-4-phenylbutyl!carbazate(ii) t-butyl-3-isopropyl-3- (2R orS,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl!carbazate (iii)t-butyl-3-(1-methyl-3-phenylpropyl)-3- 2R or S,3S)-2-hydroxy-3(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl!carbazate,(iv) 1- 2-(2-pyridyl)methoxycarbonylamino!-benzoyl-2- (2R orS,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4phenylbutyl!-2-isopropylhydrazine,(v) 1-trimethylacetyl-2- 2R orS,3S)-2-hydroxy-3(N-quinaldyl-L-asparaginyl)amino-4phenylbutyl!-2-isopropylhydrazine,(vi) 1-(t-butylamino)carbonyl-2- (2R orS,3S)-2hydroxy-3(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl!-2-isopropylhydrazine,(viii) t-butyl-3- 2R orS,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)-amino4-phenylbutyl!carbazate, and (ix) t-butyl 3-cyclohexyl-3- 2R orS,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl!carbazate, wherein the derivatives consist ofcompounds (i)-(vi), (viii) and (ix) in which the 2-hydroxy group isderivatized with a solubilizing group Px which is liable in vivo and Pxis as previously defined.
 5. A compound according to claim 4 wherein thesolubilising group Px is selected from the group consisting of##STR750##
 6. A compound according to claim 5, which compound isselected from the group consisting of:t-butyl-3-isopropyl-3- (2S,3S)-2-phosphonooxy-3-(N-quinaldyl-L-asparaginyl)-amino-4-phenylbutylcarbazateand t-butyl-3-isopropyl-3- (2S,3S)-2phosphitooxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutylcarbazate.7. The compound t-butyl 3-isopropyl-3- (2S,3S-2-phosphonooxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutylcarbazate.8. The compound t-butyl 3-isopropyl-3- (2S,3S)-2-phosphitooxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutylcarbazate.9. The pharmaceutical composition comprising an effective amount of acompound of claim 1 together with at least one pharmaceuticallyacceptable carrier, diluent, excipient and/or adjuvant.
 10. Apharmaceutical composition comprising an effective amount of a compoundof claim 2 together with at least one pharmaceutically acceptablecarrier, diluent, excipient and/or adjuvant.
 11. A pharmaceuticalcomposition comprising an effective amount of a compound of claim 3together with at least one pharmaceutically acceptable carrier, diluent,excipient and/or adjuvant.
 12. A pharmaceutical composition comprisingan effective amount of a compound of claim 4 together with at least onepharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.13. A pharmaceutical composition comprising an effective amount of acompound of claim 5 together with at least one pharmaceuticallyacceptable carrier, diluent, excipient and/or adjuvant.
 14. Apharmaceutical composition comprising an effective amount of a compoundof claim 6 together with at least one pharmaceutically acceptablecarrier, diluent, excipient and/or adjuvant.
 15. A pharmaceuticalcomposition comprising an effective amount of a compound of claim 7together with at least one pharmaceutically acceptable carrier, diluent,excipient and/or adjuvant.
 16. A pharmaceutical composition comprisingan effective amount of a compound of claim 8 together with at least onepharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.17. A method for inhibiting retroviral protease activity in a mammal,comprising administering to a mammal in need of such treatment aneffective amount of a compound according to claim
 1. 18. A method forinhibiting retroviral protease activity in a mammal, comprisingadministering to a mammal in need of such treatment an effective amountof a compound according to claim
 2. 19. A method for inhibitingretroviral protease activity in a mammal, comprising administering to amammal in need of such treatment an effective amount of a compoundaccording to claim
 3. 20. A method for inhibiting retroviral proteaseactivity in a mammal, comprising administering to a mammal in need ofsuch treatment an effective amount of a compound according to claim 4.21. A method for inhibiting retroviral protease activity in a mammal,comprising administering to a mammal in need of such treatment aneffective amount of a compound according to claim
 5. 22. A method forinhibiting retroviral protease activity in a mammal, comprisingadministering to a mammal in need of such treatment an effective amountof a compound according to claim
 6. 23. A method for inhibitingretroviral protease activity in a mammal, comprising administering to amammal in need of such treatment an effective amount of a compoundaccording to claim
 7. 24. A method for inhibiting retroviral proteaseactivity in a mammal, comprising administering to a mammal in need ofsuch treatment an effective amount of a compound according to claim 8.25. A method according to claim 17 wherein said retroviral protease isan HIV protease.
 26. A method according to claim 18 wherein saidretroviral protease is an HIV protease.
 27. A method according to claim19 wherein said retroviral protease is an HIV protease.
 28. A methodaccording to claim 20 wherein said retroviral protease is an HIVprotease.
 29. A method according to claim 21 where in said retroviralprotease is an HIV protease.
 30. A method according to claim 22 whereinsaid retroviral protease is an HIV protease.
 31. A method according toclaim 23 wherein said retroviral protease is an HIV protease.
 32. Amethod according to claim 24, wherein said retroviral protease is an HIVprotease.